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Abstract Background Many patients with advanced chronic kidney disease are referred late to renal units. This is associated with negative aspects. The purpose of the present study was to characterize late versus early referrals for renal replacement therapy including their renal disease, health care contacts and medical treatment before renal replacement therapy (RRT) and the consequences for RRT modality and mortality. Methods Nationwide cohort study including 4495 RRT patients identified in the Danish Nephrology Registry 1999–2006. The cohort was followed to end 2007 by linkage to other national registries. Late referral: follow-up ≤16 weeks in renal unit before RRT start. Cox proportional hazards models were used to estimate the relative risk of mortality or waiting list status within 365 days in late referrals versus early referrals. Results A total of 1727 (38%) incident RRT patients were referred late. Among these, 72% were treated in non-nephrology hospital departments and 91% in general practice 2 years to 16 weeks before RRT start. Fewer late referrals received recommended pre-RRT treatment as judged by renin-angiotensin-system blockade: 32% versus 57% or the D-vitamin analogue alfacalcidol: 5% versus 30% (P Conclusions Late nephrology referrals were well-known to the healthcare system before referral for RRT start and more often had near normal plasma creatinine levels within 2 years before RRT start. They infrequently received available treatment or optimal first RRT modality. An increased effort to identify these patients in the healthcare system in time for proper pre-dialysis care including preparation for RRT is needed.

Abstract Background Currently there is no disease-specific outcome measure to assess the health-related quality of life (HRQOL) of pediatric patients with Eosinophilic Esophagitis (EoE). Therefore, the objective of this qualitative study was to further develop and finalize the items and support the content validity for the new Pediatric Quality of Life Inventory™ (PedsQL™) Eosinophilic Esophagitis Module. Methods Multiphase qualitative methodology was utilized in the development of the PedsQL™ EoE Module conceptual model. Focus interview transcripts of pediatric patients with EoE and their parents and expert review were previously used to develop the initial items and domains for the PedsQL™ EoE Module. In the current investigation, utilizing the respondent debriefing methodology, cognitive interviewing was conducted individually with pediatric patients with EoE and their parents on each newly developed item. Results Information from a total of 86 participants was obtained in combination from the previous investigation and the current study. From the previous 42 focus interviews, items were developed around the domain themes of symptoms, difficulties with eating food, treatment adherence, worry about symptoms and illness, feelings of being different than family and peers, and problems discussing EoE with others. In the current study’s cognitive interviewing phase, a separate cohort of 44 participants systematically reviewed and provided feedback on each item. Items were added, modified or deleted based on this feedback. Items were finalized after this feedback from patients and parents. Conclusions Using well-established qualitative methods, the content validity of the new PedsQL™ Eosinophilic Esophagitis Module items was supported in the current investigation. In the next iterative instrument development phase, the PedsQL™ Eosinophilic Esophagitis Module is now undergoing multisite national field testing.

Abstract Background Studies on mycorrhiza associated bacteria suggest that bacterial-fungal interactions play important roles during mycorrhiza formation and affect plant health. We surveyed Streptomyces Actinobacteria, known as antibiotic producers and antagonists of fungi, from Norway spruce mycorrhizas with predominantly Piloderma species as the fungal partner. Results Fifteen Streptomyces isolates exhibited substantial variation in inhibition of tested mycorrhizal and plant pathogenic fungi (Amanita muscaria, Fusarium oxysporum, Hebeloma cylindrosporum, Heterobasidion abietinum, Heterobasidion annosum, Laccaria bicolor, Piloderma croceum). The growth of the mycorrhiza-forming fungus Laccaria bicolor was stimulated by some of the streptomycetes, and Piloderma croceum was only moderately affected. Bacteria responded to the streptomycetes differently than the fungi. For instance the strain Streptomyces sp. AcM11, which inhibited most tested fungi, was less inhibitory to bacteria than other tested streptomycetes. The determined patterns of Streptomyces-microbe interactions were associated with distinct patterns of secondary metabolite production. Notably, potentially novel metabolites were produced by strains that were less antagonistic to fungi. Most of the identified metabolites were antibiotics (e.g. cycloheximide, actiphenol) and siderophores (e.g. ferulic acid, desferroxiamines). Plant disease resistance was activated by a single streptomycete strain only. Conclusions Mycorrhiza associated streptomycetes appear to have an important role in inhibiting the growth of fungi and bacteria. Additionally, our study indicates that the Streptomyces strains, which are not general antagonists of fungi, may produce still un-described metabolites.

Abstract Background Previous attempts to measure symptoms in pediatric Eosinophilic Esophagitis (EoE) have not fully included patients and parents in the item development process. We sought to identify and validate key patient self-reported and parent proxy-reported outcomes (PROs) specific to EoE. Methods We developed methodology for focus and cognitive interviews based on the Food and Drug Administration (FDA) guidelines for PROs, the validated generic PedsQL™ guidelines, and the consolidated criteria for reporting qualitative research (COREQ). Both child (ages 8-12 and 13-18) and parent-proxy (ages 2-4, 5-7, 8-12, and 13-18) interviews were conducted. Results We conducted 75 interviews to construct the new instrument. Items were identified and developed from individual focus interviews, followed by cognitive interviews for face and content validation. Initial domains of symptom frequency and severity were developed, and open-ended questions were used to generate specific items during the focus interviews. Once developed, the instrument construct, instructions, timeframe, scoring, and specific items were systematically reviewed with a separate group of patients and their parents during the cognitive interviews. Conclusions To capture the full impact of pediatric EoE, both histologic findings and PROs need to be included as equally important outcome measures. We have developed the face and content validated Pediatric Eosinophilic Esophagitis Symptom Score (PEESS™ v2.0). The PEESS™ v2.0 metric is now undergoing multisite national field testing as the next iterative instrument development phase.

Chronic kidney disease (CKD) affects 10-15% globally and is a marked independent risk factor for cardiovascular disease. Prevalence estimations are essential for public health planning and implementation of CKD treatment strategies. This study aimed to estimate the prevalence and stages of CKD in the population-based Lolland-Falster Health Study, set in a rural provincial area with the lowest socioeconomic status in Denmark. Additionally, the study characterized participants with CKD, evaluated the overall disease recognition, including the awareness of CKD and compared it with other common conditions. Cross-sectional data were obtained from clinical examinations, biochemical analyses, and questionnaires. CKD was defined as albuminuria (urine albumin-creatinine ratio ≥30 mg/g), estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m², or by a diagnosis in the National Patient Register. Patient awareness was assessed by self-reported CKD, and overall disease recognition by either a registered hospital diagnosis or self-reported CKD. Among 16 097 adults (median age 58.6 years), CKD prevalence was 18.0% (n = 2903), with 70.1% identified by albuminuria, 28.4% by reduced eGFR, and 1.5% by a registered diagnosis alone. Of those with CKD, 98.8% had stages 1-3 (eGFR ≥30 ml/min/1.73 m²), and 1.2% had stages 4-5 (eGFR <30 ml/min/1.73 m²). Female sex, comorbidities, smoking, and low socioeconomic parameters were independently associated with CKD. Patient awareness of CKD was 4.4%, compared to >50% for hypertension and >80% for diabetes, and the overall CKD recognition (self-reported or registered diagnosis) was 7.1%. Thus, in this population-based study, CKD was highly prevalent but poorly recognized, indicating great potential for preventing CKD progression and related complications., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Public Health Association.)

Zoledronic acid is a widely used bisphosphonate for treating osteoporosis and hypercalcemia related to malignancy. It is also used to prevent bone loss induced by cancer treatment and bone metastases in various cancer types. Zoledronic acid is safe for most patients and is generally not associated with severe side effects. However, there have been reports of acute kidney impairment occurring after administration of intravenous zoledronic acid, mostly in patients with cancer (who received a high cumulative dose of this medication) or preexisting kidney impairment, and in patients with a history of nephrotoxic treatment. We report herein the cases of two patients without history of cancer, who developed dialysis-requiring acute kidney impairment after a single administration of intravenous zoledronic acid. None of the patients had previously used nephrotoxic medications, and one of them had a normal kidney function before zoledronic acid treatment. To the best of our knowledge, this report describes the first case of acute kidney impairment in a patient without risk factors. The findings of this report show that acute kidney impairment following intravenous zoledronic acid treatment can also occur in low-risk patients, highlighting the need for monitoring kidney function in all patients receiving this treatment., Competing Interests: Disclosure: no potential conflict of interest relevant to this article was reported.

Background: This study validates the application of Systematized Nomenclature of Medicine second edition (SNOMED II) codes used to describe medical kidney biopsies in Denmark in encoded form, aiming to support robust epidemiological research on the causes, treatments and prognosis of kidney diseases., Methods: Kidney biopsy reports from 1 January 1998 to 31 December 2018 were randomly extracted from the Danish National Patobank, using SNOMED codes. A 5% sample was selected, and nephrologists assessed the corresponding medical records, assigning each case the applied clinical diagnoses. Sensitivity, specificity, positive predictive values (PPV), negative predictive values and Cohen's kappa coefficient for the retrieved SNOMED codes were calculated., Results: A total of 613 kidney biopsies were included. The primary clinical disease groups were glomerular disease ( n  = 368), tubulointerstitial disease ( n  = 67), renal vascular disease ( n  = 51), diabetic nephropathy ( n  = 51) and various renal disorders ( n  = 40). Several SNOMED codes were used to describe each clinical disease group and PPV for the combined SNOMED codes were high for glomerular disease (94%), diabetic nephropathy (85%) and systemic diseases affecting the kidney (96%). Conversely, tubulointerstitial disease (62%), renal vascular disease (60%) and other renal disorders (17%) showed lower PPV., Conclusions: SNOMED codes have a high PPV for glomerular diseases, diabetic nephropathy and systemic diseases affecting the kidney, in which they could be applied for future epidemiological research., Competing Interests: No potential conflicts of interest were reported by M.M., I.B., H.D., J.W.G., H.H., K.H., P.I., K.H.R., M.B.J., D.K., F.H.M., P.R., K.E.O., F.P. and K.D.S. T.K. reports honoraria for education and consultancy from AstraZeneca. R.B. reports honoraria for education and consultancy from AstraZeneca, Bayer, Mundipharma, Vifor and Boehringer Ingelheim. M.H. reports honoraria for advisory boards for AstraZeneca, Bayer, Boeringer Ingelheim, Vifor, GSK and Novo Nordisk A/S, and education for AstraZeneca, Boeringer Ingelheim and Novo Nordisk A/S outside the scope of this manuscript. D.H. reports research grant from Vifor Pharma and Gedeon Richter, and consultancy fees and lecture fees from UCB Nordic, GSK and AstraZeneca., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: The European Renal Association (ERA) Registry collects data on kidney replacement therapy (KRT) in patients with end-stage kidney disease (ESKD). This paper is a summary of the ERA Registry Annual Report 2021, including a comparison across treatment modalities., Methods: Data was collected from 54 national and regional registries from 36 countries, of which 35 registries from 18 countries contributed individual patient data and 19 registries from 19 countries contributed aggregated data. Using this data, incidence and prevalence of KRT, kidney transplantation rates, survival probabilities and expected remaining lifetimes were calculated., Result: In 2021, 533.2 million people in the general population were covered by the ERA Registry. The incidence of KRT was 145 per million population (pmp). In incident patients, 55% were 65 years or older, 64% were male, and the most common primary renal disease (PRD) was diabetes (22%). The prevalence of KRT was 1040 pmp. In prevalent patients, 47% were 65 years or older, 62% were male, and the most common PRDs were diabetes and glomerulonephritis/sclerosis (both 16%). On 31 December 2021, 56% of patients received haemodialysis, 5% received peritoneal dialysis, and 39% were living with a functioning graft. The kidney transplantation rate in 2021 was 37 pmp, a majority coming from deceased donors (66%). For patients initiating KRT between 2012-2016, 5-year survival probability was 52%. Compared to the general population, life expectancy was 65% and 68% shorter for males and females receiving dialysis, and 40% and 43% shorter for males and females living with a functioning graft., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: The aim of this study was to identify trends in total, deceased donor (DD) and living donor (LD) kidney transplantation (KT) rates in European countries., Methods: The European Renal Association (ERA) Registry and the Global Observatory on Donation and Transplantation (GODT) databases were used to obtain the number of KTs in individual European countries between 2010 and 2018. General population counts were obtained from Eurostat or the national bureaus of statistics. The KT rate per million population (p.m.p.) and the average annual percentage change (APC) were calculated., Results: The total KT rate in the 40 participating countries increased with 1.9% annually  [95%  confidence  interval  (CI) 1.5, 2.2] from 29.6 p.m.p. in 2010 to 34.7 p.m.p. in 2018, reflecting an increase of 3.4 p.m.p. in the DD-KT rate (from 21.6 p.m.p. to 25.0 p.m.p.; APC 1.9%; 95% CI 1.3, 2.4) and of 1.5 p.m.p. in the LD-KT rate (from 8.1 p.m.p. to 9.6 p.m.p.; APC 1.6%; 95% CI 1.0, 2.3). The trends in KT rate varied widely across European countries. An East-West gradient was observed for DD-KT rate, with Western European countries performing more KTs. In addition, most countries performed fewer LD-KTs. In 2018, Spain had the highest DD-KT rate (64.6 p.m.p.) and Turkey the highest LD-KT rate (37.0 p.m.p.)., Conclusions: The total KT rate increased due to a rise in the KT rate from DDs and to a lesser extent from LDs, with large differences between individual European countries., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: Data on comorbidities in children on kidney replacement therapy (KRT) are scarce. Considering their high relevance for prognosis and treatment, this study aims to analyse the prevalence and implications of comorbidities in European children on KRT., Methods: We included data from patients <20 years of age when commencing KRT from 2007 to 2017 from 22 European countries within the European Society of Paediatric Nephrology/European Renal Association Registry. Differences between patients with and without comorbidities in access to kidney transplantation (KT) and patient and graft survival were estimated using Cox regression., Results: Comorbidities were present in 33% of the 4127 children commencing KRT and the prevalence has steadily increased by 5% annually since 2007. Comorbidities were most frequent in high-income countries (43% versus 24% in low-income countries and 33% in middle-income countries). Patients with comorbidities had a lower access to transplantation {adjusted hazard ratio [aHR] 0.67 [95% confidence interval (CI) 0.61-0.74]} and a higher risk of death [aHR 1.79 (95% CI 1.38-2.32)]. The increased mortality was only seen in dialysis patients [aHR 1.60 (95% CI 1.21-2.13)], and not after KT. For both outcomes, the impact of comorbidities was stronger in low-income countries. Graft survival was not affected by the presence of comorbidities [aHR for 5-year graft failure 1.18 (95% CI 0.84-1.65)]., Conclusions: Comorbidities have become more frequent in children on KRT and reduce their access to transplantation and survival, especially when remaining on dialysis. KT should be considered as an option in all paediatric KRT patients and efforts should be made to identify modifiable barriers to KT for children with comorbidities., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: Acute kidney injury (AKI) has been associated with cardiovascular disease, but this is sparsely studied in non-selected populations and with little attention to the effect in age and renal function. Using nationwide administrative data, we investigated the hypothesis of increased one-year risk of cardiovascular event or death associated with AKI., Methods: In a cohort study, we identified all admissions in Denmark between 2008 and 2018. AKI was defined as ≥1.5 times increase from baseline to peak creatinine during admission, or dialysis. We excluded patients with age <50 years, estimated glomerular filtration rate (eGFR) <15ml/min/1.73m 2 , renal transplantation, index-admission due to cardiovascular disease or death during index-admission. The primary outcome was cardiovascular risk within one year from discharge, which was a composite of the secondary outcomes ischemic heart disease, heart failure or stroke. To estimate risks, we applied multiple logistic regression fitted by inverse probability of censoring weighting and stratified estimations by eGFR and age. We adjusted for proteinuria in the subcohort with measurements available., Results: Among 565,056 hospital admissions, 39,569 (7.0%) cases of AKI were present. In total, 18,642 patients sustained a cardiovascular outcome. AKI was significantly associated with cardiovascular outcome with an adjusted OR [CI] of 1.33 [1.16-1.53], 1.43 [1.33-1.54], 1.23 [1.14-1.34], 1.38 [1.18-1.62] for eGFR ≥90, 60-89, 30-59 and 15-29ml/min/1.73m 2 , respectively. When omitting the outcome heart failure, these results were 1.24 [1.06-1.45], 1.22 [1.11-1.33], 1.05 [0.95-1.16], 1.25 [1.02-1.54]. Results did not change substantially in strata of age groups, in AKI stages and in the subcohort adjusted for proteinuria., Conclusion: Non-selected patients aged 50 years or above with AKI during admission had significantly higher one-year risk of cardiovascular event or death, especially, but not only due to heart failure, independent of age and eGFR., (Copyright © 2022. Published by Elsevier España, S.L.U.)

Importance: During the past decades, improvements in the prevention and management of myocardial infarction, stroke, and pulmonary embolism have led to a decline in cardiovascular mortality in the general population. However, it is unknown whether patients receiving dialysis have also benefited from these improvements., Objective: To assess the mortality rates for myocardial infarction, stroke, and pulmonary embolism in a large cohort of European patients receiving dialysis compared with the general population., Design, Setting, and Participants: In this cohort study, adult patients who started dialysis between 1998 and 2015 from 11 European countries providing data to the European Renal Association Registry were and followed up for 3 years. Data were analyzed from September 2020 to February 2022., Exposures: Start of dialysis., Main Outcomes and Measures: The age- and sex-standardized mortality rate ratios (SMRs) with 95% CIs were calculated by dividing the mortality rates in patients receiving dialysis by the mortality rates in the general population for 3 equal periods (1998-2003, 2004-2009, and 2010-2015)., Results: In total, 220 467 patients receiving dialysis were included in the study. Their median (IQR) age was 68.2 (56.5-76.4) years, and 82 068 patients (37.2%) were female. During follow-up, 83 912 patients died, of whom 7662 (9.1%) died because of myocardial infarction, 5030 (6.0%) died because of stroke, and 435 (0.5%) died because of pulmonary embolism. Between the periods 1998 to 2003 and 2010 to 2015, the SMR of myocardial infarction decreased from 8.1 (95% CI, 7.8-8.3) to 6.8 (95% CI, 6.5-7.1), the SMR of stroke decreased from 7.3 (95% CI, 7.0-7.6) to 5.8 (95% CI, 5.5-6.2), and the SMR of pulmonary embolism decreased from 8.7 (95% CI, 7.6-10.1) to 5.5 (95% CI, 4.5-6.6)., Conclusions and Relevance: In this cohort study of patients receiving dialysis, mortality rates for myocardial infarction, stroke, and pulmonary embolism decreased more over time than in the general population.

Background: Data on renal replacement therapy (RRT) for end-stage renal disease were collected by the European Renal Association (ERA) Registry via national and regional renal registries in Europe and countries bordering the Mediterranean Sea. This article provides a summary of the 2019 ERA Registry Annual Report, including data from 34 countries and additional age comparisons., Methods: Individual patient data for 2019 were provided by 35 registries and aggregated data by 17 registries. Using these data, the incidence and prevalence of RRT, the kidney transplantation activity and the survival probabilities were calculated., Results: In 2019, a general population of 680.8 million people was covered by the ERA Registry. Overall, the incidence of RRT was 132 per million population (p.m.p.). Of these patients, 62% were men, 54% were ≥65 years of age and 21% had diabetes mellitus as primary renal disease (PRD), and 84% had haemodialysis (HD), 11% had peritoneal dialysis (PD) and 5% had pre-emptive kidney transplantation as an initial treatment modality. The overall prevalence of RRT on 31 December 2019 was 893 p.m.p., with 58% of patients on HD, 5% on PD and 37% living with a kidney transplant. The overall kidney transplant rate was 35 p.m.p. and 29% of the kidney grafts were from a living donor. The unadjusted 5-year survival probability was 42.3% for patients commencing dialysis, 86.6% for recipients of deceased donor grafts and 94.4% for recipients of living donor grafts in the period 2010-14. When comparing age categories, there were substantial differences in the distribution of PRD, treatment modality and kidney donor type, and in the survival probabilities., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Background: Acute kidney injury (AKI) has been associated with cardiovascular disease, but this is sparsely studied in non-selected populations and with little attention to the effect in age and renal function. Using nationwide administrative data, we investigated the hypothesis of increased one-year risk of cardiovascular event or death associated with AKI., Methods: In a cohort study, we identified all admissions in Denmark between 2008 and 2018. AKI was defined as ≥1.5 times increase from baseline to peak creatinine during admission, or dialysis. We excluded patients with age <50 years, estimated glomerular filtration rate (eGFR) <15ml/min/1.73m 2 , renal transplantation, index-admission due to cardiovascular disease or death during index-admission. The primary outcome was cardiovascular risk within one year from discharge, which was a composite of the secondary outcomes ischemic heart disease, heart failure or stroke. To estimate risks, we applied multiple logistic regression fitted by inverse probability of censoring weighting and stratified estimations by eGFR and age. We adjusted for proteinuria in the subcohort with measurements available., Results: Among 565,056 hospital admissions, 39,569 (7.0%) cases of AKI were present. In total, 18,642 patients sustained a cardiovascular outcome. AKI was significantly associated with cardiovascular outcome with an adjusted OR [CI] of 1.33 [1.16-1.53], 1.43 [1.33-1.54], 1.23 [1.14-1.34], 1.38 [1.18-1.62] for eGFR ≥90, 60-89, 30-59 and 15-29ml/min/1.73m 2 , respectively. When omitting the outcome heart failure, these results were 1.24 [1.06-1.45], 1.22 [1.11-1.33], 1.05 [0.95-1.16], 1.25 [1.02-1.54]. Results did not change substantially in strata of age groups, in AKI stages and in the subcohort adjusted for proteinuria., Conclusion: Non-selected patients aged 50 years or above with AKI during admission had significantly higher one-year risk of cardiovascular event or death, especially, but not only due to heart failure, independent of age and eGFR., (Copyright © 2021. Published by Elsevier España, S.L.U.)

The aims of this study were to determine the frequency of dialysis and kidney transplantation and to estimate the regularity of comprehensive conservative management (CCM) for patients with kidney failure in Europe. This study uses data from the ERA-EDTA Registry. Additionally, our study included supplemental data from Armenia, Germany, Hungary, Ireland, Kosovo, Luxembourg, Malta, Moldova, Montenegro, Slovenia and additional data from Israel, Italy, Slovakia using other information sources. Through an online survey, responding nephrologists estimated the frequency of CCM (i.e. planned holistic care instead of kidney replacement therapy) in 33 countries. In 2016, the overall incidence of replacement therapy for kidney failure was 132 per million population (pmp), varying from 29 (Ukraine) to 251 pmp (Greece). On 31 December 2016, the overall prevalence of kidney replacement therapy was 985 pmp, ranging from 188 (Ukraine) to 1906 pmp (Portugal). The prevalence of peritoneal dialysis (114 pmp) and home hemodialysis (28 pmp) was highest in Cyprus and Denmark respectively. The kidney transplantation rate was nearly zero in some countries and highest in Spain (64 pmp). In 28 countries with five or more responding nephrologists, the median percentage of candidates for kidney replacement therapy who were offered CCM in 2018 varied between none (Slovakia and Slovenia) and 20% (Finland) whereas the median prevalence of CCM varied between none (Slovenia) and 15% (Hungary). Thus, the substantial differences across Europe in the frequency of kidney replacement therapy and CCM indicate the need for improvement in access to various treatment options for patients with kidney failure., (Copyright © 2021 International Society of Nephrology. All rights reserved.)

Since genes encoding epigenetic regulators are often mutated or deregulated in urothelial carcinoma (UC), they represent promising therapeutic targets. Specifically, inhibition of Class-I histone deacetylase (HDAC) isoenzymes induces cell death in UC cell lines (UCC) and, in contrast to other cancer types, cell cycle arrest in G2/M. Here, we investigated whether mutations in cell cycle genes contribute to G2/M rather than G1 arrest, identified the precise point of arrest and clarified the function of individual HDAC Class-I isoenzymes. Database analyses of UC tissues and cell lines revealed mutations in G1/S, but not G2/M checkpoint regulators. Using class I-specific HDAC inhibitors (HDACi) with different isoenzyme specificity (Romidepsin, Entinostat, RGFP966), cell cycle arrest was shown to occur at the G2/M transition and to depend on inhibition of HDAC1/2 rather than HDAC3. Since HDAC1/2 inhibition caused cell-type-specific downregulation of genes encoding G2/M regulators, the WEE1 inhibitor MK-1775 could not overcome G2/M checkpoint arrest and therefore did not synergize with Romidepsin inhibiting HDAC1/2. Instead, since DNA damage was induced by inhibition of HDAC1/2, but not of HDAC3, combinations between inhibitors of HDAC1/2 and of DNA repair should be attempted.

Objective: Transition to adult IBD care continues to be a challenge. Efficacious models of improving transition to adult care in the United States are lacking. We present data from a pilot, prospective, non-randomized, intervention implemented at IBD centers in the Midwest and Southeast United States., Design and Methods: Adolescents and young adults (AYAs; 16-20 years) with IBD and their parents completed a 4- to 5-month transition program (1 in-person group session; 4 individual telehealth sessions). Primary outcomes were feasibility (i.e., recruitment, retention, fidelity) and acceptability (i.e., program satisfaction). Secondary outcomes were changes in transition readiness, self-management skill acquisition, perceived readiness to transfer to adult care, and disease knowledge., Results: The study exceeded goals for recruitment (target N = 20; actual: 36) and retention (target: 80%; actual: 86.11%). On average, it took participants 20.91 ± 3.15 weeks to complete our 4- to 5-month intervention and there were no deviations from the study protocol. Participant ratings for overall program satisfaction, perceived helpfulness, and program length and format were positive. Increases in transition readiness, t(30) = 8.30, d = 1.49, p < .001, self-management skill acquisition, t(30) = 3.93, d = 0.70, p < .001, and disease knowledge, t(30) = 8.20, d = 1.58, p < .001 were noted. AYA- and parent-perceived transfer readiness also improved (p's < .05; d's = 0.76-1.68)., Conclusions: This article presents feasibility and acceptability data for a 4- to 5-month transition intervention. Improvements in AYA transition readiness, self-management skill acquisition, IBD knowledge, and AYA/parent perceived transfer readiness were also observed., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Registry collects data on kidney replacement therapy (KRT) via national and regional renal registries in Europe and countries bordering the Mediterranean Sea. This article summarizes the 2018 ERA-EDTA Registry Annual Report, and describes the epidemiology of KRT for kidney failure in 34 countries., Methods: Individual patient data on patients undergoing KRT in 2018 were provided by 34 national or regional renal registries and aggregated data by 17 registries. The incidence and prevalence of KRT, the kidney transplantation activity and the survival probabilities of these patients were calculated., Results: In 2018, the ERA-EDTA Registry covered a general population of 636 million people. Overall, the incidence of KRT for kidney failure was 129 per million population (p.m.p.), 62% of patients were men, 51% were ≥65 years of age and 20% had diabetes mellitus as cause of kidney failure. Treatment modality at the onset of KRT was haemodialysis (HD) for 84%, peritoneal dialysis (PD) for 11% and pre-emptive kidney transplantation for 5% of patients. On 31 December 2018, the prevalence of KRT was 897 p.m.p., with 57% of patients on HD, 5% on PD and 38% living with a kidney transplant. The transplant rate in 2018 was 35 p.m.p.: 68% received a kidney from a deceased donor, 30% from a living donor and for 2% the donor source was unknown. For patients commencing dialysis during 2009-13, the unadjusted 5-year survival probability was 42.6%. For patients receiving a kidney transplant within this period, the unadjusted 5-year survival probability was 86.6% for recipients of deceased donor grafts and 93.9% for recipients of living donor grafts., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Production of antibiotics to inhibit competitors affects soil microbial community composition and contributes to disease suppression. In this work, we characterized whether Streptomyces bacteria, prolific antibiotics producers, inhibit a soil borne human pathogenic microorganism, Streptomyces sudanensis. S. sudanensis represents the major causal agent of actinomycetoma - a largely under-studied and dreadful subcutaneous disease of humans in the tropics and subtropics. The objective of this study was to evaluate the in vitro S. sudanensis inhibitory potential of soil streptomycetes isolated from different sites in Sudan, including areas with frequent (mycetoma belt) and rare actinomycetoma cases of illness., Results: Using selective media, 173 Streptomyces isolates were recovered from 17 sites representing three ecoregions and different vegetation and ecological subdivisions in Sudan. In total, 115 strains of the 173 (66.5%) displayed antagonism against S. sudanensis with different levels of inhibition. Strains isolated from the South Saharan steppe and woodlands ecoregion (Northern Sudan) exhibited higher inhibitory potential than those strains isolated from the East Sudanian savanna ecoregion located in the south and southeastern Sudan, or the strains isolated from the Sahelian Acacia savanna ecoregion located in central and western Sudan. According to 16S rRNA gene sequence analysis, isolates were predominantly related to Streptomyces werraensis, S. enissocaesilis, S. griseostramineus and S. prasinosporus. Three clusters of isolates were related to strains that have previously been isolated from human and animal actinomycetoma cases: SD524 (Streptomyces sp. subclade 6), SD528 (Streptomyces griseostramineus) and SD552 (Streptomyces werraensis)., Conclusion: The in vitro inhibitory potential against S. sudanensis was proven for more than half of the soil streptomycetes isolates in this study and this potential may contribute to suppressing the abundance and virulence of S. sudanensis. The streptomycetes isolated from the mycetoma free South Saharan steppe ecoregion show the highest average inhibitory potential. Further analyses suggest that mainly soil properties and rainfall modulate the structure and function of Streptomyces species, including their antagonistic activity against S. sudanensis.

Objective: First, to compare QOL and illness perceptions between patients with a Fontan circulation and patients with anatomically simple defects (ie, atrial septal defects [ASD] or ventricular septal defects [VSD]). Second, to explore illness perceptions as a mediator of the association between congenital heart disease (CHD) diagnosis and QOL., Design: Cross-sectional observational study., Setting: Twenty-four cardiology centers from 15 countries across five continents., Patients: Four hundred thirty-five adult patients with congenital heart disease (177 Fontan and 258 ASD/VSD) ages 18-83 years., Outcome Measures: QOL and illness perceptions were assessed by the Satisfaction With Life Scale and the Brief Illness Perceptions Questionnaire, respectively., Results: Patients with a Fontan circulation reported lower QOL (Wald Z = -3.59, p = <.001) and more negative perceptions of their CHD (Wald Z = -7.66, p < .001) compared with patients with ASD/VSD. After controlling for demographics, anxiety, depressive symptoms, and New York Heart Association functional class, path analyses revealed a significant mediation model, αβ = 0.15, p = .002, 95% CI = 0.06-0.25, such that CHD diagnosis was indirectly related to QOL through illness perceptions., Conclusions: The Fontan sample's more negative perceptions of CHD were likely a reflection of life with a more complex defect. Illness perceptions appear to account for unique differences in QOL between groups of varying CHD complexity. Psychosocial screening and interventions may be important treatment components for patients with CHD, particularly those with Fontan circulations., (© 2018 Wiley Periodicals, Inc.)

Background: Patients on dialysis treatment or living with a transplanted kidney have several risk factors for bone fracture, especially disturbances in mineral metabolism and immunosuppressive therapy. We describe the incidence of fracture in this retrospective national Danish cohort study and explore the influence of age, gender, comorbidity and prescribed medication., Methods: By individual-level linkage between nationwide administrative registries, the risk of fracture was compared between the group of patients receiving chronic dialysis treatment and patients receiving their first renal transplant in the study period, using the Danish background population as reference group. All three groups were followed up until first fracture, emigration, death or end of study. Cox proportional hazard models with fracture as outcome were fitted to the data., Results: The hazard ratio (HR) for any fracture was 3.14 [95% confidence interval (95% CI):2.97-3.31] in the dialysis group and 1.94 (95% CI: 1.72-2.18) in the renal transplanted group. The HR remained increased, but was modified by adjustment for age, gender, comorbidity and prior fracture [dialysis group: 1.85 (95% CI: 1.75-1.95); renal transplanted group: 1.82 (95% CI: 1.62-2.06)]. Prescribed diuretics, lipid-modifying agents and proton pump inhibitors also modulated the fracture risk., Conclusions: Patients on dialysis or living with a transplanted kidney have a significantly higher risk of fracture than the Danish background population. Differences in age, gender, drug use and comorbidity only partly explain this increased risk. Further studies are warranted to explore the reason for this increased fracture risk in patients on renal replacement therapy., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Dialysis-requiring acute kidney injury (AKI) is associated with substantial mortality and risk of end-stage renal disease (ESRD). Despite considerable growth in incidence of severe AKI, information pertaining to trends in outcomes remains limited. We evaluated time trends in one year risks of ESRD and death in patients with dialysis-requiring AKI over an eight year period in Denmark., Methods: In a retrospective nationwide study based on national registers, all adults requiring acute renal replacement therapy between 2005 and 2012 were identified. Patients with preceding ESRD were excluded. Through individual-level cross-referencing of administrative registries, information pertaining to comorbidity, preceding surgical interventions, and concurrent other organ failure and sepsis was ascertained. Comparisons of period-specific one year odds ratios for ESRD and death were calculated in a multiple logistic regression model., Results: A total of 13,819 patients with dialysis-requiring AKI were included in the study. Within one year, 1,017 (7.4%) patients were registered with ESRD, and 7,908 (57.2%) patients died. The one-year rate of ESRD decreased from 9.0% between 2005 and 2006 to 6.1% between 2011 and 2012. Simultaneously, the one-year mortality rate decreased from 58.2% between 2005 and 2006 to 57.5% between 2011 and 2012. Consequently, the adjusted odds ratios for the period 2011-2012 (with the period 2005-2006 as reference) were 0.75 (0.60-0.95, p = 0.015) and 0.87 (95% CI 0.78-0.97, p = 0.010) for ESRD and death, respectively., Conclusions: In a nationwide retrospective study on time trends in one year outcomes following dialysis-requiring AKI, risk of all-cause mortality and ESRD decreased over a period of 8 years.

Background: In Western countries, black and Asian dialysis patients experience better survival compared with white patients. The aim of this study is to compare the survival of native Danish dialysis patients with that of dialysis patients originating from other countries and to explore the association between the duration of residence in Denmark before the start of dialysis and the mortality on dialysis., Methods: We performed a population-wide national cohort study of incident chronic dialysis patients in Denmark (≥18 years old) who started dialysis between 1995 and 2010., Results: In total, 8459 patients were native Danes, 344 originated from other Western countries, 79 from North Africa or West Asia, 173 from South or South-East Asia and 54 from sub-Saharan Africa. Native Danes were more likely to die on dialysis compared with the other groups (crude incidence rates for mortality: 234, 166, 96, 110 and 53 per 1000 person-years, respectively). Native Danes had greater hazard ratios (HRs) for mortality compared with the other groups {HRs for mortality adjusted for sociodemographic and clinical characteristics: 1.32 [95% confidence interval (CI) 1.14-1.54]; 2.22 [95% CI 1.51-3.23]; 1.79 [95% CI 1.41-2.27]; 2.00 [95% CI 1.10-3.57], respectively}. Compared with native Danes, adjusted HRs for mortality for Western immigrants living in Denmark for ≤10 years, >10 to ≤20 years and >20 years were 0.44 (95% CI 0.27-0.71), 0.56 (95% CI 0.39-0.82) and 0.86 (95% CI 0.70-1.04), respectively. For non-Western immigrants, these HRs were 0.42 (95% CI 0.27-0.67), 0.52 (95% CI 0.33-0.80) and 0.48 (95% CI 0.35-0.66), respectively., Conclusions: Incident chronic dialysis patients in Denmark originating from countries other than Denmark have a better survival compared with native Danes. For Western immigrants, this survival benefit declines among those who have lived in Denmark longer. For non-Western immigrants, the survival benefit largely remains over time., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Pediatric Crohn's Disease (CD) is associated with low trabecular bone mineral density (BMD), cortical area, and muscle mass. Low-magnitude mechanical stimulation (LMMS) may be anabolic. We conducted a 12-month randomized double-blind placebo-controlled trial of 10 minutes daily exposure to LMMS (30 Hz frequency, 0.3 g peak-to-peak acceleration). The primary outcomes were tibia trabecular BMD and cortical area by peripheral quantitative CT (pQCT) and vertebral trabecular BMD by QCT; additional outcomes included dual-energy X-ray absorptiometry (DXA) whole body, hip and spine BMD, and leg lean mass. Results were expressed as sex-specific Z-scores relative to age. CD participants, ages 8 to 21 years with tibia trabecular BMD <25th percentile for age, were eligible and received daily cholecalciferol (800 IU) and calcium (1000 mg). In total, 138 enrolled (48% male), and 121 (61 active, 60 placebo) completed the 12-month trial. Median adherence measured with an electronic monitor was 79% and did not differ between arms. By intention-to-treat analysis, LMMS had no significant effect on pQCT or DXA outcomes. The mean change in spine QCT trabecular BMD Z-score was +0.22 in the active arm and -0.02 in the placebo arm (difference in change 0.24 [95% CI 0.04, 0.44]; p = 0.02). Among those with >50% adherence, the effect was 0.38 (95% CI 0.17, 0.58, p < 0.0005). Within the active arm, each 10% greater adherence was associated with a 0.06 (95% CI 0.01, 1.17, p = 0.03) greater increase in spine QCT BMD Z-score. Treatment response did not vary according to baseline body mass index (BMI) Z-score, pubertal status, CD severity, or concurrent glucocorticoid or biologic medications. In all participants combined, height, pQCT trabecular BMD, and cortical area and DXA outcomes improved significantly. In conclusion, LMMS was associated with increases in vertebral trabecular BMD by QCT; however, no effects were observed at DXA or pQCT sites. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Introduction: Dialysis-requiring acute kidney injury is a severe illness associated with poor prognosis. However, information pertaining to incidence rates and prevalence of risk factors remains limited in spite of increasing focus. We evaluate time trends of incidence rates and changing patterns in prevalence of comorbidities, concurrent medication, and other risk factors in nationwide retrospective cohort study., Materials and Methods: All patients with dialysis-requiring acute kidney injury were identified between January 1st 2000 and December 31st 2012. By cross-referencing data from national administrative registries, the association of changing patterns in dialysis treatment, comorbidity, concurrent medication and demographics with incidence of dialysis-requiring acute kidney injury was evaluated., Results: A total of 18,561 adult patients with dialysis-requiring AKI were identified between 2000 and 2012. Crude incidence rate of dialysis-requiring AKI increased from 143 per million (95% confidence interval, 137-144) in 2000 to 366 per million (357-375) in 2006, and remained stable hereafter. Notably, incidence of continuous veno-venous hemodialysis (CRRT) and use of acute renal replacement therapy in elderly >75 years increased substantially from 23 per million (20-26) and 328 per million (300-355) in 2000, to 213 per million (206-220) and 1124 per million (1076-1172) in 2012, respectively. Simultaneously, patient characteristics and demographics shifted towards increased age and comorbidity., Conclusions: Although growth in crude incidence rate of dialysis-requiring AKI stabilized in 2006, continuous growth in use of CRRT, and acute renal replacement therapy of elderly patients >75 years, was observed. Our results indicate an underlying shift in clinical paradigm, as opposed to unadulterated growth in incidence of dialysis-requiring AKI.

Background: The balance between stroke reduction and increased bleeding associated with antithrombotic therapy among patients with atrial fibrillation (AF) and chronic kidney disease (CKD) is controversial., Objectives: This study assessed the risk associated with CKD in individual CHA₂DS₂-VASc (Congestive heart failure; Hypertension; Age ≥75 years; Diabetes mellitus; previous Stroke, transient ischemic attack, or thromboembolism; Vascular disease; Age 65 to 74 years; Sex category) strata and the net clinical benefit of warfarin in patients with AF and CKD in a nationwide cohort., Methods: By individual-level linkage of nationwide Danish registries, we identified all patients discharged with nonvalvular AF from 1997 to 2011. The stroke risk associated with non-end-stage CKD and end-stage CKD (e.g., patients on renal replacement therapy [RRT]) was estimated using Cox regression analyses. The net clinical benefit of warfarin was assessed using 4 endpoints: a composite endpoint of death/hospitalization from stroke/bleeding; a composite endpoint of fatal stroke/fatal bleeding; cardiovascular death; and all-cause death., Results: From nonvalvular AF patients (n = 154,259), we identified 11,128 patients (7.2%) with non-end-stage CKD and 1,728 (1.1%) receiving RRT. In all CHA₂DS₂-VASc risk groups, RRT was independently associated with a higher risk of stroke/thromboembolism, from a 5.5-fold higher risk in patients with CHA₂DS₂-VASc score = 0 to a 1.6-fold higher risk in patients with CHA₂DS₂-VASc score ≥2. In patients receiving RRT with CHA₂DS₂-VASc score ≥2, warfarin was associated with lower risk of all-cause death (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.72 to 0.99). In non-end-stage CKD patients with CHA₂DS₂-VASc score ≥2, warfarin was associated with a lower risk of a composite outcome of fatal stroke/fatal bleeding (HR: 0.71, 95% CI: 0.57 to 0.88), a lower risk of cardiovascular death (HR: 0.80, 95% CI: 0.74 to 0.88), and a lower risk of all-cause death (HR: 0.64, 95% CI: 0.60 to 0.69)., Conclusions: CKD is associated with a higher risk of stroke/thromboembolism across stroke risk strata in AF patients. High-risk CKD patients (CHA₂DS₂-VASc ≥2) with AF benefit from warfarin treatment for stroke prevention., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The aim of the present study was to evaluate clopidogrel treatment after incident myocardial infarction (MI) in patients with and without chronic kidney disease (CKD)., Methods and Results: By linking nation-wide registries, information about patients admitted with incident MI was found. Primary endpoints were all-cause and cardiovascular (CV) mortality, a composite of all-cause mortality and recurrent MI, and a composite of fatal and nonfatal bleedings. Effect of clopidogrel use versus clopidogrel nonuse was estimated using an adjusted Cox's regression model stratified according to percutaneous coronary intervention (PCI) treatment.A total of 69 082 incident MI patients in the period 2002-2011 were included. Clopidogrel treatment was associated with hazard ratios (HRs) for the combined endpoint of all-cause mortality and recurrent MI in PCI-treated patients of 0.90 (95% confidence interval [CI], 0.47 to 1.72) in renal replacement therapy (RRT) patients, 0.59 (95% CI: 0.40 to 0.88) in non-end-stage CKD patients and 0.69 (95% CI, 0.61 to 0.77) in patients without kidney disease (P for interaction=0.60). In patients not treated with PCI, HRs were 0.90 (95% CI, 0.68 to 1.21) in RRT patients, 0.86 (95% CI, 0.75 to 0.99) in non-end-stage CKD patients, and 0.91 (95% CI, 0.87 to 0.95) in patients without kidney disease (P for interaction=0.74). An increase in bleeding events (not significant) was noted for clopidogrel-treated patients not undergoing PCI and for non-end-stage CKD patients undergoing PCI, whereas clopidogrel was associated with less bleedings in PCI-treated RRT patients and patients without kidney disease., Conclusions: During a 1-year follow-up, after MI, clopidogrel was associated with improved outcomes in patients with non-end-stage CKD. Even though no effect difference, compared to patients without CKD, was observed, the benefit associated with the use of clopidogrel after MI in patients requiring RRT is less clear., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: We first describe a patient who developed urosepsis from an ordinary urinary tract infection. In this case, the new hematological parameters of immature leukocytes, that is, the high-fluorescence lymphocyte cell (HFLC) and immature granulocyte (IG) counts peaked early, whereas the established infection parameters, that is, C-reactive protein (CRP) and total white blood cell count showed less dynamic regarding infection and therapy., Methods: To investigate this phenomenon in greater detail, the novel parameters HFLC and IG counts are investigated retrospectively in a cohort of 38 patients who were admitted to the anesthesia intensive care unit. Three groups of patients have been analyzed and compared: patients without signs of infection, patients with limited infections, and patients with sepsis. Data were collected with a Sysmex XE-5000 hematological analyzer., Results: In patients (n = 22) without any signs of infection, both values are very low. In patients with limited local infections (n = 10), moderate elevations of the IG and HFLC counts are seen. In patients with sepsis (n = 6), the IG and HFLC counts are significantly higher., Conclusion: The total IG count seems to be useful for distinguishing a septic patient from a nonseptic (P < 0.004). Hematological parameters have the advantage of being measured easily during routine blood cell analysis., (© 2014 Wiley Periodicals, Inc.)

Objective: To document current clinical practices for medical regimen adherence assessment and intervention in the field of pediatric psychology., Methods: 113 members of the Society of Pediatric Psychology completed an anonymous online survey that assessed use of adherence assessments and interventions in clinical practice, barriers and facilitators to their use, and preferred resources for obtaining information on adherence assessments and interventions., Results: Respondents reported using a range of adherence assessment and intervention strategies, some of which are evidence-based. Barriers to implementing these clinical strategies included time constraints and lack of familiarity with available clinical tools. Respondents reported that education about effective clinical tools would facilitate their use of adherence assessments and interventions., Conclusions: Future research and clinical efforts in adherence should consider developing practical tools for clinical practice, making accessible resources to promote dissemination of these tools, and increase understanding of clinician implementation of adherence assessments and interventions.

Background: The Danish National Registry on Regular Dialysis and Transplantation (NRDT) provides systematic information on the epidemiology and treatment of end-stage chronic kidney disease in Denmark. It is therefore of major importance that the registry is valid and complete. The aim of the present study was to evaluate the registration of incident patients on chronic renal replacement therapy (RRT)., Methods: Incident patients on chronic RRT in the period 2001-2004 were identified in NRDT and in the National Patient Registry, which contains information on hospital admissions and treatments. In the National Patient Registry, identification of patients was as follows: patients receiving the procedure of dialysis during a minimum of 90 days and for a minimum of 12 times or the procedure of renal transplantation. Only patients with at least 2 years of dialysis-free interval before and never being transplanted were included. The completeness of NRDT was calculated as the percentage of new patients on chronic RRT registered in the National Patient Registry also found in NRDT. Validity of data in NRDT was assessed by information from medical records and analysed using kappa statistics., Results: Completeness of NRDT: Of 3020 patients registered in the National Patient Registry as incident chronic RRT patients, 97.2% were found in NRDT but 22.5% with another year of entry. There were no differences in completeness between hospitals or regions. Validity of NRDT: Validity of common renal diagnoses and RRT modality was high: diabetic nephropathy (kappa = 0.98), adult polycystic kidney disease (kappa = 0.95), chronic glomerulonephritis (kappa = 0.78) and RRT modality (kappa = 0.94). The diagnosis CKD of unknown aetiology and type of diabetes were less valid (kappa = 0.62, 0.60 and 0.73, respectively). The date of RRT start had also high validity., Conclusions: Completeness of incident patient registration in NRDT was highly acceptable. Validity of incident patient data was also good, except for type of diabetes.