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Accurate diagnosis of the causes of chest pain and dyspnea remain challenging. In this preliminary observational study with a 5-year follow-up, we attempted to find a simplified approach to selecting patients with chest pain needing immediate care based on the initial evaluation in ED. During a 24-month period were randomly selected 301 patients and a conditional inference tree (CIT) was used as the basis of the prognostic rule. Common diagnoses were musculoskeletal chest pain (27%), ACS (19%) and panic attack (12%). Using variables of ACS symptoms we estimated the likelihood of ACS based on a CIT to be high at 91% (32), low at 4% (198) and intermediate at 20.5–40% in (71) patients. Coronary catheterization was performed within 24 hours in 91% of the patients with ACS. A culprit lesion was found in 79%. Follow-up (median 4.2 years) information was available for 70% of the patients. Of the 164 patients without ACS who were followed up, 5 were treated with revascularization for stable angina pectoris, 2 were treated with revascularization for myocardial infarction, and 25 died. Although a simple triage decision tree could theoretically help to efficient select patients needing immediate care we need also to be vigilant for those presenting with atypical symptoms.

Abstract Background Urolithiasis is one of the most common conditions seen in emergency departments (ED) worldwide, with an increasing frequency in geriatric patients (>65 years). Given the high costs of emergency medical urolithiasis treatment, the need to optimise management is obvious. We aimed to determine risk factors for hospitalisation and evaluate diagnostic and emergency treatment patterns by ED physicians in geriatric urolithiasis patients to assist in optimising treatment. Methods After receiving ethics committee approval, we examined the records of emergency urolithiasis admissions to our ED between January 2000 and December 2010 to determine risk factors for hospitalisation and to evaluate current diagnostic and emergency treatment patterns in geriatric urolithiasis patients. Results 1,267 consecutive patients at least 20 years of age with confirmed urolithiasis (1,361 ED visits) and complete follow-up data were analyzed. Geriatric patients comprised 10% of urolithiasis patients with more than half of them experiencing their first urolithiasis episode at ED admission. Although stone site, side and size did not significantly differ between groups, urinary stone disease was more severe in the elderly. The risk of severe complications correlated with increasing age, female sex and diabetes mellitus. Geriatric patients had a two-fold greater likelihood of being hospitalised. A significantly lower percentage of geriatric patients received combined analgesic therapy for pain management (37% vs. 64%, p = Conclusion Geriatric patients with urolithiasis have a higher morbidity than younger patients and may be undertreated concerning analgetic and expulsive treatment in ED.

Abstract Background Although renal involvement in advanced haematological malignancies is common, glomerulonephritis associated with lymphoproliferative disorders is rare, and the related pathogenetic mechanisms are still poorly understood. We present a rare case of chronic lymphocytic leukaemia(CLL)-associated focal segmental glomerulosclerosis with nephrotic-range proteinuria. Case presentation A 53-year-old Caucasian man, previously healthy, with no history of hypertension, alcohol use or smoking presented with rapid weight gain, massive peripheral oedema, and hypertension. Laboratory findings included a white blood cell count of 49,800 cells/mm3 with an absolute lymphocyte count of 47,000 cells/mm3, serum albumin of 2.3 g/dL, urea 65 mg/dL, and creatinine 1.5 mg/dL. A 24-hour urine collection contained 7.1 g protein and significant haematuria. A peripheral blood smear showed mature lymphocytosis and smudge cells. Diagnostic imaging showed mild paraaortic lymphadenopathy with no renal abnormalities. Bone marrow aspiration and trephine biopsy showed diffuse and focal infiltration with B-CLL lymphocytes. Percutaneous renal biopsy revealed total sclerosis in 3/21(14%) of the glomeruli and focal and segmental solidification and sclerosis in 4/21 (19%) glomeruli. A regimen of fludarabine, cyclophosphamide and rituximab was successful in inducing remission of the CLL and clinical resolution of the nephritic-range proteinuria. Conclusions A multidisciplinary approach to monitor both the malignancy and the glomerular lesions is crucial for the optimal management of paraneoplastic glomerulonephritis. Although chemotherapy with fludarabine, cyclophosphamide and rituximab successfully treated CLL-associated nephrotic syndrome in our patient, further studies are required to confirm efficacy in this setting.

Abstract Normal pregnancy corresponds to a procoagulant state. Acute myocardial infarction during pregnancy is rare, yet considering the low non-pregnant risk score of childbearing women it is still surprisingly frequent. We report a case of postpartum recurrent non-ST elevation myocardial infarction in a 40-year-old caucasian woman with essential thrombocythaemia in the presence of a positive JAK-2 mutation and an elevated anti-cardiolipin IgM antibody titer. In the majority of cases of myocardial infarction in pregnancy or in the peripartal period, atherosclerosis, a thrombus or coronary artery dissection is observed. The combination of essential thrombocythaemia and elevated anti-cardiolipin IgM antibody titer in the presence of several cardiovascular risk factors seems to be causative in our case. In conclusion, with the continuing trend of childbearing at older ages, rare or unlikely conditions leading to severe events such as myocardial infarction must be considered in pregnant women.

Ribosomal DNA (rDNA) encodes the ribosomal RNA genes and represents an intrinsically unstable genomic region. However, the underlying mechanisms and implications for genome integrity remain elusive. Here, we use Bloom syndrome (BS), a rare genetic disease characterized by DNA repair defects and hyper-unstable rDNA, as a model to investigate the mechanisms leading to rDNA instability. We find that in Bloom helicase (BLM) proficient cells, the homologous recombination (HR) pathway in rDNA resembles that in nuclear chromatin; it is initiated by resection, replication protein A (RPA) loading and BRCA2-dependent RAD51 filament formation. However, BLM deficiency compromises RPA-loading and BRCA1/2 recruitment to rDNA, but not RAD51 accumulation. RAD51 accumulates at rDNA despite depletion of long-range resection nucleases and rDNA damage results in micronuclei when BLM is absent. In summary, our findings indicate that rDNA is permissive to RAD51 accumulation in the absence of BLM, leading to micronucleation and potentially global genomic instability., (© 2024. The Author(s).)

TIMP-2 and IGFBP7 have been identified and validated for the early detection of renal injury in critically ill patients, but data on recovery of allograft function after kidney transplantation (KTx) are scarce. In a prospective observational multicenter cohort study of renal transplant recipients, urinary [TIMP-2] × [IGFBP7] was evaluated daily from day 1 to 7 after KTx. Different stages of early graft function were defined: immediate graft function (IGF) (decrease ≥ 10% in serum creatinine (s-crea) within 24 h post KTx); slow graft function (SGF) (decrease in s-crea < 10% within 24 h post KTx); and delayed graft function (DGF) (any dialysis needed within the first week after KTx). A total of 186 patients were analyzed. [TIMP-2] × [IGFBP7] was significantly elevated as early as day 1 in patients with DGF compared to SGF and IGF. ROC analysis of [TIMP-2] × [IGFBP7] at day 1 post-transplant for event "Non-DGF" revealed a cut-off value of 0.9 (ng/mL) 2 /1000 with a sensitivity of 87% and a specificity of 71%. The positive predictive value for non-DGF was 93%. [TIMP-2] × [IGFBP7] measured at day 1 after KTx can predict early recovery of transplant function and is therefore a valuable biomarker for clinical decision making.

Drug repurposing is a versatile strategy to improve current therapies. Disulfiram has long been used in the treatment of alcohol dependency and multiple clinical trials to evaluate its clinical value in oncology are ongoing. We have recently reported that the disulfiram metabolite diethyldithiocarbamate, when combined with copper (CuET), targets the NPL4 adapter of the p97VCP segregase to suppress the growth of a spectrum of cancer cell lines and xenograft models in vivo. CuET induces proteotoxic stress and genotoxic effects, however important issues concerning the full range of the CuET-evoked tumor cell phenotypes, their temporal order, and mechanistic basis have remained largely unexplored. Here, we have addressed these outstanding questions and show that in diverse human cancer cell models, CuET causes a very early translational arrest through the integrated stress response (ISR), later followed by features of nucleolar stress. Furthermore, we report that CuET entraps p53 in NPL4-rich aggregates leading to elevated p53 protein and its functional inhibition, consistent with the possibility of CuET-triggered cell death being p53-independent. Our transcriptomics profiling revealed activation of pro-survival adaptive pathways of ribosomal biogenesis (RiBi) and autophagy upon prolonged exposure to CuET, indicating potential feedback responses to CuET treatment. The latter concept was validated here by simultaneous pharmacological inhibition of RiBi and/or autophagy that further enhanced CuET's tumor cytotoxicity, using both cell culture and zebrafish in vivo preclinical models. Overall, these findings expand the mechanistic repertoire of CuET's anti-cancer activity, inform about the temporal order of responses and identify an unorthodox new mechanism of targeting p53. Our results are discussed in light of cancer-associated endogenous stresses as exploitable tumor vulnerabilities and may inspire future clinical applications of CuET in oncology, including combinatorial treatments and focus on potential advantages of using certain validated drug metabolites, rather than old, approved drugs with their, often complex, metabolic profiles., (© 2023. The Author(s).)

Background: Metabolic acidosis is common in kidney transplant recipients and is associated with declining graft function. Sodium bicarbonate treatment effectively corrects metabolic acidosis, but no prospective studies have examined its effect on graft function. Therefore, we aimed to test whether sodium bicarbonate treatment would preserve graft function and slow the progression of estimated glomerular filtration rate (GFR) decline in kidney transplant recipients., Methods: The Preserve-Transplant Study was a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial at three University Hospitals in Switzerland (Zurich, Bern, and Geneva), which recruited adult (aged ≥18 years) male and female long-term kidney transplant recipients if they had undergone transplantation more than 1 year ago. Key inclusion criteria were an estimated GFR between 15 mL/min per 1·73 m 2 and 89 mL/min per 1·73 m 2 , stable allograft function in the last 6 months before study inclusion (<15% change in serum creatinine), and a serum bicarbonate of 22 mmol/L or less. We randomly assigned patients (1:1) to either oral sodium bicarbonate 1·5-4·5 g per day or matching placebo using web-based data management software. Randomisation was stratified by study centre and gender using a permuted block design to guarantee balanced allocation. We did multi-block randomisation with variable block sizes of two and four. Treatment duration was 2 years. Acid-resistant soft gelatine capsules of 500 mg sodium bicarbonate or matching 500 mg placebo capsules were given at an initial dose of 500 mg (if bodyweight was <70 kg) or 1000 mg (if bodyweight was ≥70 kg) three times daily. The primary endpoint was the estimated GFR slope over the 24-month treatment phase. The primary efficacy analyses were applied to a modified intention-to-treat population that comprised all randomly assigned participants who had a baseline visit. The safety population comprised all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT03102996., Findings: Between June 12, 2017, and July 10, 2019, 1114 kidney transplant recipients with metabolic acidosis were assessed for trial eligibility. 872 patients were excluded and 242 were randomly assigned to the study groups (122 [50%] to the placebo group and 120 [50%] to the sodium bicarbonate group). After secondary exclusion of two patients, 240 patients were included in the intention-to-treat analysis. The calculated yearly estimated GFR slopes over the 2-year treatment period were a median -0·722 mL/min per 1·73 m 2 (IQR -4·081 to 1·440) and mean -1·862 mL/min per 1·73 m 2 (SD 6·344) per year in the placebo group versus median -1·413 mL/min per 1·73 m 2 (IQR -4·503 to 1·139) and mean -1·830 mL/min per 1·73 m 2 (SD 6·233) per year in the sodium bicarbonate group (Wilcoxon rank sum test p=0·51; Welch t-test p=0·97). The mean difference was 0·032 mL/min per 1·73 m 2 per year (95% CI -1·644 to 1·707). There were no significant differences in estimated GFR slopes in a subgroup analysis and a sensitivity analysis confirmed the primary analysis. Although the estimated GFR slope did not show a significant difference between the treatment groups, treatment with sodium bicarbonate effectively corrected metabolic acidosis by increasing serum bicarbonate from 21·3 mmol/L (SD 2·6) to 23·0 mmol/L (2·7) and blood pH from 7·37 (SD 0·06) to 7·39 (0·04) over the 2-year treatment period. Adverse events and serious adverse events were similar in both groups. Three study participants died. In the placebo group, one (1%) patient died from acute respiratory distress syndrome due to SARS-CoV-2 and one (1%) from cardiac arrest after severe dehydration following diarrhoea with hypotension, acute kidney injury, and metabolic acidosis. In the sodium bicarbonate group, one (1%) patient had sudden cardiac death., Interpretation: In adult kidney transplant recipients, correction of metabolic acidosis by treatment with sodium bicarbonate over 2 years did not affect the decline in estimated GFR. Thus, treatment with sodium bicarbonate should not be generally recommended to preserve estimated GFR (a surrogate marker for graft function) in kidney transplant recipients with chronic kidney disease who have metabolic acidosis., Funding: Swiss National Science Foundation., Competing Interests: Declaration of interests NM received lecture fees from Forum für Medizinische Fortbildung and Boehringer Ingelheim. AR received support for attending meetings and travel expenses from Salmon Pharma and Astellas Pharma. CAW received honoraria from Medice, Kyowa Kirin, Advicenne, and Ardelyx. RPW received honoraria from OM Pharma. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Urine flow cytometry (UFC) analyses urine samples and determines parameter counts. We aimed to predict different types of urine culture growth, including mixed growth indicating urine culture contamination., Methods: A retrospective cohort study (07/2017-09/2020) was performed on pairs of urine samples and urine cultures obtained from adult emergency department patients. The dataset was split into a training (75%) and validation set (25%). Statistical analysis was performed using a machine learning approach with extreme gradient boosting to predict urine culture growth types (i.e., negative, positive, and mixed) using UFC parameters obtained by UF-4000, sex, and age., Results: In total, 3835 urine samples were included. Detection of squamous epithelial cells, bacteria, and leukocytes by UFC were associated with the different types of culture growth. We achieved a prediction accuracy of 80% in the three-class approach. Of the n = 126 mixed cultures in the validation set, 11.1% were correctly predicted; positive and negative cultures were correctly predicted in 74.0% and 96.3%., Conclusions: Significant bacterial growth can be safely ruled out using UFC parameters. However, positive urine culture growth (rule in) or even mixed culture growth (suggesting contamination) cannot be adequately predicted using UFC parameters alone. Squamous epithelial cells are associated with mixed culture growth.

Disulfiram (DSF), an established alcohol-aversion drug, is a candidate for repurposing in cancer treatment. DSF's antitumor activity is supported by preclinical studies, case reports, and small clinical trials; however, ongoing clinical trials of advanced-stage cancer patients encounter variable results. Here, we show that one reason for the inconsistent clinical effects of DSF may reflect interference by other drugs. Using a high-throughput screening and automated microscopy, we identify cannabidiol, an abundant component of the marijuana plant used by cancer patients to mitigate side effects of chemotherapy, as a likely cause of resistance to DSF. Mechanistically, in cancer cells, cannabidiol triggers the expression of metallothioneins providing protective effects by binding heavy metal-based substances including the bis-diethyldithiocarbamate-copper complex (CuET). CuET is the documented anticancer metabolite of DSF, and we show here that the CuET's anticancer toxicity is effectively neutralized by metallothioneins. Overall, this work highlights an example of undesirable interference between cancer therapy and the concomitant usage of marijuana products. In contrast, we report that insufficiency of metallothioneins sensitizes cancer cells toward CuET, suggesting a potential predictive biomarker for DSF repurposing in oncology., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Late post-transplant Pneumocystis jirovecii pneumonia (PcP) has been reported in many renal transplant recipients (RTRs) centers using universal prophylaxis. Specific features of PcP compared to other respiratory infections in the same population are not well reported. We analyzed clinical, laboratory, administrative and radiological data of all confirmed PcP cases between January 2009 and December 2014. To identify factors specifically associated with PcP, we compared clinical and laboratory data of RTRs with non-PcP. Over the study period, 36 cases of PcP were identified. Respiratory distress was more frequent in PcP compared to non-PcP (tachypnea: 59%, 20/34 vs. 25%, 13/53, p = 0.0014; dyspnea: 70%, 23/33 vs. 44%, 24/55, p = 0.0181). In contrast, fever was less frequent in PcP compared to non-PcP pneumonia (35%, 11/31 vs. 76%, 42/55, p = 0.0002). In both cohorts, total lymphocyte count and serum sodium decreased, whereas lactate dehydrogenase (LDH) increased at diagnosis. Serum calcium increased in PcP and decreased in non-PcP. In most PcP cases (58%, 21/36), no formal indication for restart of PcP prophylaxis could be identified. Potential transmission encounters, suggestive of interhuman transmission, were found in 14/36, 39% of patients. Interhuman transmission seems to contribute importantly to PcP among RTRs. Hypercalcemia, but not elevated LDH, was associated with PcP when compared to non-PcP.

Background: Up to a fourth of patients at emergency department (ED) presentation suffer from acute deterioration of renal function, which is an important risk factor for bleeding events in patients on oral anticoagulation therapy. We hypothesized that outcomes of patients, bleeding characteristics, therapy, and outcome differ between direct oral anticoagulants (DOACs) and vitamin-K antagonists (VKAs)., Methods: All anticoagulated patients older than 17 years with an impaired kidney function treated for an acute haemorrhage in a large Swiss university ED from 01.06.2012 to 01.07.2017 were included in this retrospective cohort study. Patient, treatment, and bleeding characteristics as well as outcomes (length of stay ED, intensive care unit and in-hospital admission, ED resource consumption, in-hospital mortality) were compared between patients on DOAC or VKA anticoagulant., Results: In total, 158 patients on DOAC and 419 patients on VKA with acute bleeding and impaired renal function were included. The renal function in patients on VKA was significantly worse compared to patients on DOAC (VKA: median 141 μmol/L vs. DOAC 132 μmol/L, p = 0.002). Patients on DOAC presented with a smaller number of intracranial bleeding compared to VKA (14.6% DOAC vs. 22.4% VKA, p = 0.036). DOAC patients needed more emergency endoscopies (15.8% DOAC vs, 9.1% VKA, p = 0.020) but less interventional emergency therapies to stop the bleeding (13.9% DOAC vs. 22.2% VKA, p = 0.027). Investigated outcomes did not differ significantly between the two groups., Conclusions: DOAC patients were found to have a smaller proportional incidence of intracranial bleedings, needed more emergency endoscopies but less often interventional therapy compared to patients on VKA. Adapted treatment algorithms are a potential target to improve care in patients with DOAC., (© 2021. The Author(s).)

Background: Hyponatremia is one of the most common electrolyte disorders observed in hospitalized and ambulatory patients. Hyponatremia is associated with increased falls, fractures, prolonged hospitalisation and mortality. The clinical importance of hyponatremia in the renal transplant field is not well established, so the aim of this study was to determine the relationships between hyponatremia and mortality as main outcome and renal function decline and graft loss as secondary outcome among a prospective cohort of renal transplant recipients., Methods: This prospective cohort study included 1315 patients between 1 May 2008 and 31 December 2014. Hyponatremia was defined as sodium concentration below 136 mmol/L at 6 months after transplantation. The main endpoint was mortality. A secondary composite endpoint was also defined as: rapid decline in renal function (≥5 mL/min/1.73 m 2 drop of the eGFR/year), graft loss or mortality., Results: Mean sodium was 140 ± 3.08 mmol/L. 97 patients displayed hyponatremia with a mean of 132.9 ± 3.05 mmol/L. Hyponatremia at 6 months after transplantation was associated neither with mortality (HR: 1.02; p = 0.97, 95% CI: 0.47-2.19), nor with the composite outcome defined as rapid decline in renal function, graft loss or mortality (logrank test p = 0.9)., Conclusions: Hyponatremia 6 months after transplantation is not associated with mortality in kidney allograft patients.

Objective: To prospectively evaluate the diagnostic accuracy of contrast enhanced ultrasound (CEUS) and MRI compared to computed tomography (CT) as the current gold standard for the characterization of cystic renal lesions using the Bosniak classification., Methods: Between July 2014 and October 2017 we prospectively enrolled patients with cystic renal lesions. Based on the Bosniak classification of complex renal lesions (≥BII-F) we evaluated the accuracy of observed agreement by Cohen's Kappa coefficient and calculated sensitivity, specificity, positive and negative predictive values (PPV/NPV) between the three imaging modalities CT, MRI and CEUS., Results: We evaluated 65 cystic renal lesions in 48 patients (median age 63 years, range 36-91 years; 18 females, 30 males). According to CT 29 (47%) of the cystic renal lesions were classified as complex. The agreement between CEUS and CT in the classification of complex cystic lesions was fair (agreement 50.8%, Kappa 0.31), and was excellent between MRI and CT (agreement 93.9%, Kappa 0.88). Compared to CT, CEUS and MRI had a sensitivity of 100% and 96.6%, a specificity of 33.3% and 91.7%, a PPV of 54.7% and 90.3%, and a NPV of 100% and 97.1% with an accuracy of 63.1% and 93.8% respectively., Conclusion: CEUS has an excellent sensitivity and NPV and represents a promising non-invasive screening tool for renal cystic lesions. The classification of complex renal cysts based on MRI and CT scans correlated closely., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate differences in chest computed tomography (CT) and chest radiographs (CXRs) of Pneumocystis jirovecii pneumonia (PJP) between renal transplant recipients (RTRs) and human immunodeficiency virus (HIV)-positive patients., Methods: From 2005 to 2012, 84 patients with PJP (RTR n = 24; HIV n = 60) were included in this retrospective multicentre study. Written informed consent was obtained. CT scans and CXRs were recorded within 2 weeks after the onset of symptoms. PJP diagnosis was confirmed either by cytology/histology or successful empirical treatment. Two blinded radiologists analysed the conventional chest films and CT images, and recorded the radiological lung parenchyma patterns, lymph node enlargement and pleural pathologies (pneumothorax, effusion). The radiological features of the two subgroups were compared., Results: Consolidations and solid nodules prevailed on CT in RTRs (91.7 &plusmn; 5.6% vs 58.3 &plusmn; 6.4% with HIV, p = 0.019 and 91.7 &plusmn; 5.6% vs 51.6 &plusmn; 6.5% with HIV, p = 0.005). HIV-positive patients with PJP showed more atelectasis (41.7 &plusmn; 6.4% vs 4.2 &plusmn; 4.1% in RTRs, p = 0.017) and hilar lymph node enlargement (23.3 &plusmn; 5.5% vs 0.0 &plusmn; 0.0% in RTRs, p = 0.088). Ground glass opacification was found in all cases. Pneumothorax was a rare complication, occurring in 3% of the HIV-positive patients; no pneumothorax was found in the RTRs. On CXR, the basal lungs were more affected in HIV-positive patients as compared with RTRs (p = 0.024)., Conclusions: PJP on CT differs substantially between RTRs and HIV-positive patients. Physicians should be aware of such differences in order not to delay treatment, particularly in renal transplant recipients.

Background: Little evidence exists regarding the long-term impact of acute kidney injury (AKI) during index hospitalisation for acute myocardial infarction (AMI). We prospectively assessed the long-term prognostic significance of the occurrence of in-hospital AKI in a multicentre cohort of patients admitted with AMI., Methods: Data were obtained from 518 AMI patients with a median follow-up of 5.6 (IQR 4.6-6.5) years. Patients were followed up regarding the occurrence of death, major adverse cardiovascular events (MACE), and any deterioration in kidney function., Results: From the study cohort, 84 patients (16%) had developed AKI at discharge during index hospitalisation. 96 patients died during follow-up, MACE occurred in 90 patients, and 30 patients showed evidence of deterioration in kidney function. Patients with AKI at hospital discharge had a three-fold increased mortality risk (HR 3.2, 95% CI 2.1-4.8; P < 0.001). This association was independent of possible confounding by variables that could influence prognosis (HR 1.9 95% CI 1.1-3.2; P = 0.028) evident only up to three years during follow-up. During long-term follow-up, patients with AKI during their index hospitalisation had a significantly (P = 0.027) higher incidence of MACE (26%) than those who did not develop AKI (15%). Patients with AKI had a higher incidence of deteriorating kidney function (10%) than those without AKI (5%) during follow-up, but this difference was not significant (P = 0.124)., Conclusions: Our findings emphasise in addition to the need for appropriate long term follow-up in such patients, an increased mortality and morbidity during the first three years after the index event., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Bacterium and leucocyte counts in urine can be measured by urine flow cytometry (UFC). They are used to predict significant bacterial growth in urine culture and to diagnose infections of the urinary tract. However, little information is available on appropriate UFC cut-off values for bacterium and leucocyte counts in specific clinical presentations., Objective: To develop, validate, and evaluate adapted cut-off values that result in a high negative predictive value for significant bacterial growth in urine culture in common clinical presentation subgroups., Methods: This is a single center, retrospective, observational study with data from patients of the emergency department of Bern University Hospital, Switzerland, with suspected infections of the urinary tract. The patients presented with different symptoms, and urine culture and urine flow cytometry were performed. For different clinical presentations, the patients were grouped by (i) age (>65 years), (ii) sex, (iii) clinical symptoms (e.g., fever or dysuria), and (iv) comorbidities such as diabetes and immunosuppression. For each group, cut-off values were developed, validated, and analyzed using different strategies, i.e., linear discriminant analysis (LDA) and Youden's index, and were compared with known cut-offs and cut-offs optimized for sensitivity., Results: 613 patients were included in the study. Significant bacterial growth in urine culture depended on clinical presentation and ranged from 32.3% in male patients to 61.5% in patients with urinary frequency. In all clinical presentations, the predictive accuracy of UFC leucocyte and UFC bacterium counts was good for significant bacterial growth in urine culture (AUC ≥ 0.88). The adapted LDA 95 equations did not exhibit consistently high sensitivity. However, the in-house cut-offs (test positive if UFC leucocytes > 17/ μ L or UFC bacteria > 125/ μ L) were highly sensitive (>90%). In female, younger, and dysuric patients, even higher cut-offs for UFC leucocytes (169/ μ L, 169/ μ L, and 205/ μ L) exhibited high sensitivity. Specificity was insufficient (<0.9) for all tested cut-offs., Conclusions: For various clinical presentations, significant bacterial growth in urine culture can be excluded if flow cytometry measurements give a bacterial count of ≤125/ μ L or a leucocyte count of ≤17/ μ L. In female patients, dysuric patients, and patients younger than ≤65 years, the leucocyte cut-off can be increased to 170/ μ L.

Background: Although chronic kidney disease (CKD) patients are particularly prone to malnutrition, systematic nutritional screening is rarely routinely performed during hospitalization. The primary aim of this study was to determine the prevalence of malnutrition (as captured by the nutritional screening score NRS) in hospitalized CKD patients and explore the impact of malnutrition on hospital mortality., Methods: All patients admitted to the tertiary nephrology department of the University hospital of Bern Inselspital over a period of 12 months were included in this observational study. The risk for malnutrition was assessed within 24h of admission by the NRS. Demographic, clinical, and outcome data were extracted from the patient database. The primary outcome was in-hospital mortality. The secondary outcomes were length of hospitalization and hospitalization costs. Multilevel mixed-effect logistic regression model analysis was performed to determine the association of in-hospital mortality and risk of malnutrition (NRS score≥3)., Results: We included 696 eligible hospitalizations of 489 CKD patients. Hospitalized patients had a median age of 64 years (interquartile range (IQR), 52-72), 35.6% were at risk of malnutrition (NRS≥3). After adjustment for the identified confounders (Case weight, Barthel index, and CKD stage) multivariate analysis confirmed an independent and significant association between higher in-hospital mortality with NRS≥3 [OR 2.92 (95% CI: 1.33-6.39), P<0.001]. Furthermore, in multivariate analysis the risk of malnutrition was associated with longer length of hospitalization [Geometric mean ratio: 1.8 (95% CI: 1.5-2.0), p<0.001] and with increased hospitalization costs [Geometric mean ratio: 1.7 (95% CI: 1.5-1.9), p<0.001])., Conclusions: Malnutrition in CKD patients, as captured by NRS>3, is highly prevalent among hospitalized CKD patient and associated with prolonged hospital stay and increased in-hospital mortality., Competing Interests: Mo Saffarini (ReSurg SA) performed language edition and proofreading of the first draft, had no relevant financial interests, activities, relationships, or affiliations that would be considered a conflict of interest with regard to this manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Accelerated bone loss occurs rapidly following renal transplantation due to intensive immunosuppression and persistent hyperparathyroidism. In renal transplant recipients (RTRs) due to the hyperparathyroidism the non-dominant forearm is often utilized as a peripheral measurement site for dual-energy x-ray absorptiometry (DXA) measurements. The forearm is also the site of previous created distal arteriovenous fistulas (AVF). Although AVF remain patent long after successful transplantation, there are no data available concerning their impact on radial bone DXA measurements., Methods: In this cross-sectional study we performed DXA in 40 RTRs with preexisting distal AVF (RTRs-AVF) to assess areal bone mineral density (aBMD) differences between both forearms (three areas) and compared our findings to patients with chronic kidney disease (CKD, n = 40), pre-emptive RTRs (RTRs-pre, n = 15) and healthy volunteers (n = 20). In addition, we assessed relevant demographic, biochemical and clinical aspects., Results: We found a marked radial asymmetry between the forearms in RTRs with preexisting AVF. The radial aBMD at the distal AVF forearm was lower compared to the contralateral forearm, resulting in significant differences for all three areas analyzed: the Rad-1/3: median (interquartile range) in g/cm2, Rad-1/3: 0.760 (0.641-0.804) vs. 0.742 (0.642, 0.794), p = 0.016; ultradistal radius, Rad-UD: 0.433 (0.392-0.507) vs. 0.420 (0.356, 0.475), p = 0.004; and total radius, Rad-total: 0.603 (0.518, 0.655) vs. 0.599 (0.504, 0.642), p = 0.001). No such asymmetries were observed in any other groups. Lower aBMD in AVF forearm subregions resulted in misclassification of osteoporosis., Conclusions: In renal transplant recipients, a previously created distal fistula may exert a negative impact on the radial bone leading to significant site-to-site aBMD differences, which can result in diagnostic misclassifications., Competing Interests: This PIs of this Study (SA, UH) received an independent medical education grant by AMGEN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no other consultancy fees, employment, patents, products in development or marketed products which are in any relationship with this manuscript and the medical education grant by Amgen. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Graft survival after kidney transplantation has significantly improved within the last decades but there is a substantial number of patients with declining transplant function and graft loss. Over the past years several studies have shown that metabolic acidosis plays an important role in the progression of Chronic Kidney Disease (CKD) and that alkalinizing therapies significantly delayed progression of CKD. Importantly, metabolic acidosis is highly prevalent in renal transplant patients and a recent retrospective study has shown that metabolic acidosis is associated with increased risk of graft loss and patient death in kidney transplant recipients. However, no prospective trial has been initiated yet to test the role of alkali treatment on renal allograft function., Methods: The Preserve-Transplant Study is an investigator-initiated, prospective, patient-blinded, multi-center, randomized, controlled phase-IV trial with two parallel-groups comparing sodium bicarbonate to placebo. The primary objective is to test if alkali treatment will preserve kidney graft function and diminish the progression of CKD in renal transplant patients by assesing the change in eGFR over 2 years from baseline. Additionally we want to investigate the underlying pathomechanisms of nephrotoxicity of metabolic acidosis., Discussion: This study has the potential to provide evidence that alkali treatment may slow or reduce the progression towards graft failure and significantly decrease the rate of end stage renal disease (ESRD), thus prolonging long-term graft survival. The implementation of alkali therapy into the drug regimen of kidney transplant recipients would have a favorable risk-benefit ratio since alkali supplements are routinely used in CKD patients and represent a well-tolerated, safe and cost-effective treatment., Trial Registration: ClinicalTrials.gov NCT03102996 . Trial registration was completed on April 6, 2017.

Aim: In the coming years, older individuals will comprise an increasing share of emergency department (ED) admissions, due to the unprecedented and continuing demographic changes. The primary aim of the present study was to identify causes and risk factors for ED admission and hospitalizations in the oldest old., Methods: We analyzed data of consecutive patients aged in their mid 90s and older (aged ≥94 years) admitted to the ED department of the University Hospital of Bern, Bern, Switzerland, between 2000 and 2010. Using multivariate logistic regression, we explored relevant demographic and clinical characteristics of patients visiting the ED, in association with hospitalization and fractures., Results: A total of 352 ED admissions occurred during the study period. The majority of patients (85%) were admitted from home, and most (63%) admissions resulted in hospitalization. Hospital admissions were frequently related to injuries from falls (42%). Risk factors for hospitalization were fractures, the number of comorbidities (measured by the Charlson Comorbidity Index) and hypertension. Major risk factors for fractures were female sex, benzodiazepine use and the diagnosis of dementia., Conclusions: Most ED visits of older adults aged in their mid 90s and older were due to falls and fractures, and resulted in hospitalization. The present findings clearly emphasize the need for further investigations of drug prescription patterns and fracture prevention in such patients. Geriatr Gerontol Int 2018; 18: 415-420., (© 2017 Japan Geriatrics Society.)

Background: Systemic lupus erythematosus (SLE) is associated with severe cardiovascular complications. The T50 score is a novel functional blood test quantifying calcification propensity in serum. High calcification propensity (or low T50) is a strong and independent determinant of all-cause mortality in various patient populations., Methods: A total of 168 patients with ≥ 4 American College of Rheumatology (ACR) diagnostic criteria from the Swiss Systemic lupus erythematosus Cohort Study (SSCS) were included in this analysis. Serum calcification propensity was assessed using time-resolved nephelometry., Results: The cohort mainly consisted of female (85%), middle-aged (43±14 years) Caucasians (77%). The major determinants of T50 levels included hemoglobin, serum creatinine and serum protein levels explaining 43% of the variation at baseline. Integrating disease activity (SELENA-SLEDAI) into this multivariate model revealed a significant association between disease activity and T50 levels. In a subgroup analysis considering only patients with active disease (SELENA-SLEDAI score ≥4) we found a negative association between T50 and SELENA-SLEDAI score at baseline (Spearman's rho -0.233, P = 0.02)., Conclusions: Disease activity and T50 are closely associated. Moreover, T50 levels identify a subgroup of SLE patients with ongoing systemic inflammation as mirrored by increased disease activity. T50 could be a promising biomarker reflecting SLE disease activity and might offer an earlier detection tool for high-risk patients.

Arteriosklerosis and "osteoporosis" in patients with chronic kidney disease: same same, but different! Abstract. Vascular calcifications should be considered a dynamic process sharing many similarities with bone formation. Even though the underlying pathophysiology of renal insufficiency-related vascular and bone disorders has just begun to be revealed, they appear to be closely related to each other and together appear to have an enormous impact on cardiovascular morbidity and mortality. Vascular and bone disorders are highly prevalent in the general population. In patients with chronic kidney disease (CKD), not only the progression of these disorders appears to be accelerated, but they also appear to be governed by different pathophysiological mechanisms, and hence should be managed differently. One should be especially cautious about the use of some "standard drugs" like calcium supplements or bisphosphonates when treating patients with CKD. Unfortunately, no evidence-based therapeutic options of vascular and bone disorders in patients with CKD are yet available with proven positive effect on hard endpoints such as overall mortality or fracture risk.

Chronic kidney disease (CKD) is a major health problem worldwide, but not enough is known about effective self-management interventions. In this qualitative study, we explore how outpatients with CKD Stages 1-5 (without renal replacement therapy) and their family members experienced an individually tailored CKD counseling service led by an advanced practice nurse (APN). Using thematic analysis, 10 pair interviews (N = 20) were conducted and analyzed stepwise. Findings revealed iterative processes along the course of the disease. Participants struggled with an incomprehensible diagnosis. An APN assisted them in their efforts to master CKD. The APN offered information, insights, and understanding. This support helped the families achieve a new outlook and filled some gaps in CKD care. Future development of the service should focus on slowing down CKD progression more effectively. Healthcare providers are encouraged to acknowledge the importance of ongoing guidance and the continuity of care in treating patients with CKD., Competing Interests: The author reported no actual or potential conflict of interest in relation to this continuing nursing education activity., (Copyright© by the American Nephrology Nurses Association.)

Background: Patients with acute myocardial infarction are at high risk for acute kidney injury. Novel biomarkers that can predict acute kidney injury in AMI may allow timely interventions. C-terminal fragment of agrin (CAF), a proteoglycan of the glomerular and tubular basement membrane, have been recently associated with rapid renal function deterioration and proximal tubular dysfunction. It is unknown whether elevated CAF levels may serve as a novel AKI biomarker in patients presenting with AMI., Methods: In 436 persons enrolled in a multicenter prospective observational cohort study of patients with acute myocardial infarction, we measured plasma and urine levels of several kidney injury biomarkers including CAF, neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18) and cystatin-C.The relationship between biomarker levels at baseline and the development of AKI and long-term mortality were analyzed after adjustment for demographic and clinical variables., Results: AKI incidence was up to 15% during hospitalization. The predictive accuracy for AKI of urinary CAF was similar to NGAL and superior to other tested kidney injury biomarkers. In a multivariate model that included all possible confounding variables only urinary CAF continued to be an independent marker for AKI (OR 1.35 95%CI 1.05 -1.74). During the 2 years follow-up, only plasma CAF levels remained a significant independent predictor of mortality (OR 2.5 95%CI 1.02-6.2; P = 0.04)., Conclusions: Elevated CAF levels are associated with AKI in patients with acute myocardial infarction. Our study provides preliminary evidence that CAF levels may predict AKI and mortality after AMI in low risk patients with relative preserved kidney function at baseline.

Background and Objectives: Patients receiving hemodialysis are at risk of cardiovascular events. A novel blood test (T 50 test) determines the individual calcification propensity of blood., Design, Setting, Participants, & Measurements: T 50 was determined in 2785 baseline serum samples of patients receiving hemodialysis enrolled in the Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) trial and the T 50 results were related to patient outcomes., Results: Serum albumin, bicarbonate, HDL cholesterol, and creatinine were the main factors positively/directly and phosphate was the main factor negatively/inversely associated with T 50 . The primary composite end point (all-cause mortality, myocardial infarction [MI], hospitalization for unstable angina, heart failure, or peripheral vascular event [PVE]) was reached in 1350 patients after a median follow-up time of 619 days. After adjustments for confounding, a lower T 50 was independently associated with a higher risk of the primary composite end point as a continuous measure (hazard ratio [HR] per 1 SD lower T 50 , 1.15; 95% confidence interval [95% CI], 1.08 to 1.22; P<0.001). Furthermore, lower T 50 was associated with a higher risk in all-cause mortality (HR per 1 SD lower T 50 , 1.10; 95% CI, 1.02 to 1.17; P=0.001), MI (HR per 1 SD lower T 50 , 1.38; 95% CI, 1.19 to 1.60; P<0.001), and PVE (HR per 1 SD lower T 50 , 1.22; 95% CI, 1.05 to 1.42; P=0.01). T 50 improved risk prediction (integrated discrimination improvement and net reclassification improvement, P<0.001 and P=0.001) of the primary composite end point., Conclusions: Blood calcification propensity was independently associated with the primary composite end point, all-cause mortality, MI, and PVE in the EVOLVE study and improved risk prediction. Prospective trials should clarify whether T 50 -guided therapies improve outcomes., (Copyright © 2017 by the American Society of Nephrology.)

Background: Pneumocystis jirovecii pneumonia (PCP) is a frequent opportunistic infection in immunocompromised patients. In literature, presentation and outcome of PCP differs between patients with human immunodeficiency virus (HIV) infection and renal transplant recipients (RTRs)., Methods: We conducted a cross-sectional study of patients with PCP based on the HIV and renal transplant registries at our institution. Radiological and clinical data from all confirmed PCP cases between 2005 and 2012 were compared., Results: Forty patients were included: 16 with HIV and 24 RTRs. Radiologically, HIV patients had significantly more areas of diffuse lung affection (81% HIV vs. 25% RTR; p = 0.02), more ground glass nodules 5-10 mm (69% vs. 4%; p = <0.001) and enlarged hilar lymph nodes were found only in HIV patients (44%). Cough and dyspnea were the most common clinical signs (>80%) in both groups. Duration from illness onset to hospital presentation was longer in the HIV patients (median of 18 vs. 10 days (p = 0.02)), implying a less fulminant clinical course. Sixty percent of PCP cases in RTRs occurred >12 months after transplantation. Lengths of hospitalization, admission rates to the intensive care unit, and requirements for mechanical ventilation were similar. Outcome in both groups was favourable., Conclusions: While important differences in radiological presentation of PCP between HIV patients and RTRs were found, clinical presentation was similar. PCP only rarely presented with fulminant respiratory symptoms requiring ICU admission, with similar results and outcomes for HIV patients and RTRs. Early diagnosis and treatment is mandatory for clinical success., Competing Interests: The authors have declared that no competing interests exist.

The substantial evidence base for interventional ultrasound approaches to renal diagnostic sampling and therapeutic access exists. This review comments on the evidence-based recommendations on ultrasound-guided renal access which have been published recently within the framework of Guidelines on Interventional Ultrasound (InVUS) of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) from a clinical practice point of view. Specific aspects of tissue handling and workup, procedural approach and patient interaction are discussed. Indications, contraindications, risk factors and methods to reduce these risks are considered.

Calciprotein particle maturation time (T50) in serum is a novel measure of individual blood calcification propensity. To determine the clinical relevance of T50 in renal transplantation, baseline serum T50 was measured in a longitudinal cohort of 699 stable renal transplant recipients and the associations of T50 with mortality and graft failure were analyzed over a median follow-up of 3.1 years. Predictive value of T50 was assessed for patient survival with reference to traditional (Framingham) risk factors and the calcium-phosphate product. Serum magnesium, bicarbonate, albumin, and phosphate levels were the main determinants of T50, which was independent of renal function and dialysis vintage before transplant. During follow-up, 81 (12%) patients died, of which 38 (47%) died from cardiovascular causes. Furthermore, 45 (6%) patients developed graft failure. In fully adjusted models, lower T50 values were independently associated with increased all-cause mortality (hazard ratio, 1.43; 95% confidence interval, 1.11 to 1.85; P=0.006 per SD decrease) and increased cardiovascular mortality (hazard ratio, 1.55; 95% confidence interval, 1.04 to 2.29; P=0.03 per SD decrease). In addition to age, sex, and eGFR, T50 improved prognostication for all-cause mortality, whereas traditional risk factors or calcium-phosphate product did not. Lower T50 was also associated with increased graft failure risk. The associations of T50 with mortality and graft failure were confirmed in an independent replication cohort. In conclusion, reduced serum T50 was associated with increased risk of all-cause mortality, cardiovascular mortality, and graft failure and, of all tested parameters, displayed the strongest association with all-cause mortality in these transplant recipients., (Copyright © 2016 by the American Society of Nephrology.)

Background: Diabetes is the leading cause of CKD in the developed world. C-terminal fragment of agrin (CAF) is a novel kidney function and injury biomarker. We investigated whether serum CAF predicts progression of kidney disease in type 2 diabetics., Methods: Serum CAF levels were measured in 71 elderly patients with diabetic nephropathy using a newly developed commercial ELISA kit (Neurotune®). Estimated glomerular filtration rate (eGFR) and proteinuria in spot urine were assessed at baseline and after 12 months follow up. The presence of end stage renal disease (ESRD) was evaluated after 24 months follow-up. Correlation and logistic regression analyses were carried out to explore the associations of serum CAF levels with GFR, proteinuria, GFR loss and incident ESRD. Renal handling of CAF was tested in neurotrypsin-deficient mice injected with recombinant CAF., Results: We found a strong association of serum CAF levels with eGFR and a direct association with proteinuria both at baseline (r = 0.698, p<0.001 and r = 0. 287, p = 0.02) as well as after 12 months follow-up (r = 0.677, p<0.001 and r = 0.449, p<0.001), respectively. Furthermore, in multivariate analysis, serum CAF levels predicted eGFR decline at 12 months follow-up after adjusting for known risk factors (eGFR, baseline proteinuria) [OR (95%CI) = 4.2 (1.2-14.5), p = 0.024]. In mice, injected CAF was detected in endocytic vesicles of the proximal tubule., Conclusion: Serum CAF levels reflect renal function and are highly associated with eGFR and proteinuria at several time points. Serum CAF was able to predict subsequent loss of renal function irrespective of baseline proteinuria in diabetic nephropathy. CAF is likely removed from circulation by glomerular filtration and subsequent endocytosis in the proximal tubule. These findings may open new possibilities for clinical trial design, since serum CAF levels may be used as a selection tool to monitor kidney function in high-risk patients with diabetic nephropathy.