Search

Objective To increase the likelihood of finding a causative genetic variant in patients with a focal segmental glomerulosclerosis (FSGS) lesion, clinical and histologic characteristics were analyzed. Patients and Methods Individuals 18 years and older with an FSGS lesion on kidney biopsy evaluated at Mayo Clinic from November 1, 1999, through October 31, 2019, were divided into 4 groups based on clinical and histologic characteristics: primary FSGS, secondary FSGS with known cause, secondary FSGS without known cause, and undetermined FSGS. A targeted gene panel and a customized gene panel retrieved from exome sequencing were performed. Results The overall rate of detection of a monogenic cause was 42.9% (21/49). Individuals with undetermined FSGS had the highest rate of positivity (87.5%; 7/8) followed by secondary FSGS without an identifiable cause (61.5%; 8/13) and secondary FSGS with known cause (33.3%; 5/15). Four of 5 (80%) individuals in the latter group who had positive genetic testing results also had a family history of kidney disease. Univariate analysis showed that family history of kidney disease (odds ratio [OR], 13.8; 95% CI, 3.7 to 62.4; P Conclusion In adults with FSGS lesions, proper selection of patients increases the rate of positive genetic testing significantly. The majority of individuals with undetermined FSGS in whom the clinical presentation and histologic parameters are discordant had a genetic diagnosis.

Background: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1’s natural absence in laboratory animals makes studying its pathobiology challenging. Methods: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. Results: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR

Introduction Cystic expansion damaging the parenchyma is thought to lead to end-stage kidney disease (ESKD) in autosomal dominant polycystic kidney disease (ADPKD). Here we characterized genotypic and phenotypic attributes of ADPKD at time of ESKD. Methods This is a retrospective cross-sectional study of patients with ADPKD with ESKD evaluated at Mayo Clinic with available abdominal computed tomography (CT) or magnetic resonance imaging (MRI). Kidney volumes were measured (total kidney volume adjusted for height [HtTKV]), Mayo Image Class (MIC) calculated, ADPKD genotype determined, and clinical and laboratory features obtained from medical records. Results Differences in HtTKV at ESKD were associated with patient age and sex; older patients and women had smaller HtTKV at ESKD. HtTKV at ESKD was observed to be 12.3% smaller with each decade of age (P < 0.01); but significant only in women (17.8%, P < 0.01; men 6.9%, P = 0.06). Patients with onset of ESKD at 61 years had different characteristics, with a shift from youngest to oldest in male to female enrichment, MIC from 1D/1E to 1B/1C, likely fully penetrant PKD1 mutations from 95% to 42%, and presence of macrovascular disease from 8% to 40%. Macrovascular disease was associated with smaller kidneys in female patients. Conclusion HtTKV at ESKD was smaller with advancing age in patients with ADPKD, particularly in women. These novel findings provide insight into possible underlying mechanisms leading to ESKD, which differ between younger and older individuals. Cystic growth is the predominant mechanism in younger patients with ESKD, whereas aging-related factors, including vascular disease, becomes potentially important as patients age., Graphical abstract

The application of deep learning for automated segmentation (delineation of boundaries) of histologic primitives (structures) from whole slide images can facilitate the establishment of novel protocols for kidney biopsy assessment. Here, we developed and validated deep learning networks for the segmentation of histologic structures on kidney biopsies and nephrectomies. For development, we examined 125 biopsies for Minimal Change Disease collected across 29 NEPTUNE enrolling centers along with 459 whole slide images stained with Hematoxylin & Eosin (125), Periodic Acid Schiff (125), Silver (102), and Trichrome (107) divided into training, validation and testing sets (ratio 6:1:3). Histologic structures were manually segmented (30048 total annotations) by five nephropathologists. Twenty deep learning models were trained with optimal digital magnification across the structures and stains. Periodic Acid Schiff-stained whole slide images yielded the best concordance between pathologists and deep learning segmentation across all structures (F-scores: 0.93 for glomerular tufts, 0.94 for glomerular tuft plus Bowman's capsule, 0.91 for proximal tubules, 0.93 for distal tubular segments, 0.81 for peritubular capillaries, and 0.85 for arteries and afferent arterioles). Optimal digital magnifications were 5X for glomerular tuft/tuft plus Bowman's capsule, 10X for proximal/distal tubule, arteries and afferent arterioles, and 40X for peritubular capillaries. Silver stained whole slide images yielded the worst deep learning performance. Thus, this largest study to date adapted deep learning for the segmentation of kidney histologic structures across multiple stains and pathology laboratories. All data used for training and testing and a detailed online tutorial will be publicly available.

We studied sources of variation between countries in per-capita mortality from COVID-19 (caused by the SARS-CoV-2 virus). Potential predictors of per-capita coronavirus-related mortality in 200 countries by May 9, 2020 were examined, including age, gender, obesity prevalence, temperature, urbanization, smoking, duration of the outbreak, lockdowns, viral testing, contact-tracing policies, and public mask-wearing norms and policies. Multivariable linear regression analysis was performed. In univariate analysis, the prevalence of smoking, per-capita gross domestic product, urbanization, and colder average country temperature were positively associated with coronavirus-related mortality. In a multivariable analysis of 196 countries, the duration of the outbreak in the country, and the proportion of the population aged 60 years or older were positively associated with per-capita mortality, whereas duration of mask-wearing by the public was negatively associated with mortality (all P < 0.001). Obesity and less stringent international travel restrictions were independently associated with mortality in a model which controlled for testing policy. Viral testing policies and levels were not associated with mortality. Internal lockdown was associated with a nonsignificant 2.4% reduction in mortality each week (P = 0.83). The association of contact-tracing policy with mortality was not statistically significant (P = 0.06). In countries with cultural norms or government policies supporting public mask-wearing, per-capita coronavirus mortality increased on average by just 16.2% each week, as compared with 61.9% each week in remaining countries. Societal norms and government policies supporting the wearing of masks by the public, as well as international travel controls, are independently associated with lower per-capita mortality from COVID-19.

Background Pain is the highest prioritized patient-reported outcome in people with autosomal dominant polycystic kidney disease (ADPKD) but remains infrequently and inconsistently measured in clinical trials and poorly managed in clinical settings. A recently completed systematic review of pain in ADPKD identified 26 different outcome measures. None of these measures were considered appropriate as a core outcome measure due to the lack of patient-important dimensions, inadequate content, relatively long duration of completion time and limited evidence to support psychometric robustness. Methods We convened an international Standardized Outcomes in Nephrology–Polycystic Kidney Disease consensus workshop involving 21 patients/caregivers and 40 health professionals (clinicians, nurses, researchers, policy makers and industry representatives) from 18 countries to discuss the identification or development of a core outcome measure for pain. Results Four themes were identified highlighting fundamental issues for the measurement of pain in ADPKD: distressing and disrupting life participation; variability and ambiguity in defining pain; stigma, frustration and adaptation to pain; and ensuring validity and feasibility of pain measures. Conclusions Existing measures were found to be insufficient in capturing pain as a core outcome and there was consensus on the need for a new validated measure that is simple, succinct and addresses the impact of pain on life participation. This measure will facilitate the appropriate prioritization of pain in all trials and guide clinical decision making in people with ADPKD.

Introduction Heterogeneity of nephrotic diseases and a lack of validated biomarkers limits interventions and reduces the ability to examine outcomes. Urinary CD80 is a potential biomarker for minimal change disease (MCD) steroid-sensitive nephrotic syndrome (NS). We investigated and validated a CD80 enzyme-linked immunosorbent assay (ELISA) in urine in a large cohort with a variety of nephrotic diseases. Methods A commercial CD80 ELISA was enhanced and analytically validated for urine. Patients were from Mayo Clinic (307) and Nephrotic Syndrome Study Network Consortium (NEPTUNE; 104) as follows: minimal change disease (MCD, 56), focal segmental glomerulosclerosis (FSGS, 92), lupus nephritis (LN, 25), IgA nephropathy (IgAN, 20), membranous nephropathy (MN, 49), autosomal dominant polycystic kidney disease (ADPKD, 10), diabetic nephropathy (DN; 106), pyuria (19), and controls (34). Analysis was by Kruskal−Wallis test, generalized estimating equation (GEE) models, and receiver operating characteristic (AUC) curve. Results Urinary CD80/creatinine values were highest in MCD compared to other glomerular diseases and were increased in DN with proteinuria >2 compared to controls (control = 36 ng/g; MCD = 139 ng/g, P < 0.01; LN = 90 ng/g, P < 0.12; FSGS = 66 ng/g, P = 0.18; DN = 63, P = 0.03; MN = 69 ng/g, P = 0.33; ng/g, P = 0.07; IgA = 19 ng/g, P = 0.09; ADPKD = 42, P = 0.36; and pyuria 31, P = 0.20; GEE, median, P vs. control). In proteinuric patients, CD80 concentration appears to be independent of proteinuria levels, suggesting that it is unrelated to nonspecific passage across the glomeruli. CD80/creatinine values were higher in paired relapse versus remission cases of MCD and FSGS (P < 0.0001, GEE). Conclusion Using a validated ELISA, urinary CD80 levels discriminate MCD from other forms of NS (FSGS, DN, IgA, MN) and primary from secondary FSGS., Graphical abstract

BackgroundClassification of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies. This approach does not reflect underlying disease biology, limiting the ability to predict progression or treatment response.MethodsSystems biology approaches were used to categorize patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) based on kidney biopsy tissue transcriptomics across three cohorts and assessed association with clinical outcomes. Patient-level tissue pathway activation scores were generated using differential gene expression. Then, functional enrichment and non-invasive urine biomarker candidates were identified. Biomarkers were validated in kidney organoid models and single nucleus RNA-seq (snRNAseq) from kidney biopsies.ResultsTranscriptome-based categorization identified three subgroups of patients with shared molecular signatures across independent North American, European and African cohorts. One subgroup demonstrated worse longterm outcomes (HR 5.2, p = 0.001) which persisted after adjusting for diagnosis and clinical measures (HR 3.8, p = 0.035) at time of biopsy. This subgroup’s molecular profile was largely (48%) driven by tissue necrosis factor (TNF) activation and could be predicted based on levels of TNF pathway urinary biomarkers TIMP-1 and MCP-1 and clinical features (correlation 0.63, p ConclusionsMolecular profiling identified a patient subgroup within nephrotic syndrome with poor outcome and kidney TNF pathway activation. Clinical trials using non-invasive biomarkers of pathway activation to target therapies are currently being evaluated.Significance StatementMechanistic, targeted therapies are urgently needed for patients with nephrotic syndrome. The inability to target an individual’s specific disease mechanism using currently used diagnostic parameters leads to potential treatment failure and toxicity risk. Patients with focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) were grouped by kidney tissue transcriptional profiles and a subgroup associated with poor outcomes defined. The segregation of the poor outcome group was driven by tumor necrosis factor (TNF) pathway activation and could be identified by urine biomarkers, MCP1 and TIMP1. Based on these findings, clinical trials utilizing non-invasive biomarkers of pathway activation to target therapies, improve response rates and facilitate personalized treatment in nephrotic syndrome have been initiated.

ObjectivesCOVIDTrach is a UK multicentre prospective cohort study project that aims to evaluate the outcomes of tracheostomy in patients with COVID-19 receiving mechanical ventilation and record the incidence of SARS-CoV-2 infection among healthcare workers involved in the procedure.DesignData on patient demographic, clinical history and outcomes were entered prospectively and updated over time via an online database (REDCap). Clinical variables were compared with outcomes, with logistic regression used to develop a model for mortality. Participants recorded whether any operators tested positive for SARS-CoV-2 within 2 weeks of the procedure.SettingUK National Health Service departments involved in treating patients with COVID-19 receiving mechanical ventilation.ParticipantsThe cohort comprised 1605 tracheostomy cases from 126 UK hospitals collected between 6 April and 26 August 2020.Main outcome measuresMortality following tracheostomy, successful wean from mechanical ventilation and length of time from tracheostomy to wean, discharge from hospital, complications from tracheostomy, reported SARS-CoV-2 infection among operators.ResultsThe median time from intubation to tracheostomy was 15 days (IQR 11, 21). 285 (18%) patients died following the procedure. 1229 (93%) of the survivors had been successfully weaned from mechanical ventilation at censoring and 1049 (81%) had been discharged from hospital. Age, inspired oxygen concentration, positive end-expiratory pressure setting, fever, number of days of ventilation before tracheostomy, C reactive protein and the use of anticoagulation and inotropic support independently predicted mortality. Six reports were received of operators testing positive for SARS-CoV-2 within 2 weeks of the procedure.ConclusionsTracheostomy appears to be safe in mechanically ventilated patients with COVID-19 and to operators performing the procedure and we identified clinical parameters that are predictive of mortality.Trial registration numberThe study is registered with ClinicalTrials.Gov (NCT04572438).

Background The updated Veterans Aging Cohort Study (VACS) Index 2.0 combines general and human immunodeficiency virus (HIV)–specific biomarkers to generate a continuous score that accurately discriminates risk of mortality in diverse cohorts of persons with HIV (PWH), but a score alone is difficult to interpret. Using data from the North American AIDS Cohort Collaboration (NA-ACCORD), we translate VACS Index 2.0 scores into validated probability estimates of mortality. Methods Because complete mortality ascertainment is essential for accurate calibration, we restricted analyses to cohorts with mortality from the National Death Index or equivalent sources. VACS Index 2.0 components were ascertained from October 1999 to April 2018. Mortality was observed up to March 2019. Calibration curves compared predicted (estimated by fitting a gamma model to the score) to observed mortality overall and within subgroups: cohort (VACS/NA-ACCORD subset), sex, age 500 copies/mL, CD4 count Results Among 37230 PWH in VACS and 8061 PWH in the NA-ACCORD subset, median age was 53 and 44 years; 3% and 19% were women; and 48% and 39% were black. Discrimination in NA-ACCORD (C-statistic = 0.842 [95% confidence interval {CI}, .830–.854]) was better than in VACS (C-statistic = 0.813 [95% CI, .809–.817]). Predicted and observed mortality largely overlapped in VACS and the NA-ACCORD subset, overall and within subgroups. Conclusions Based on this validation, VACS Index 2.0 can reliably estimate probability of all-cause mortality, at various follow-up times, among PWH in North America.

Objective: To describe first episodes of bacterial cholangitis complicating autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD) and to identify risk factors for cholangitis episodes among patients with ADPKD-associated polycystic liver disease (PLD). Patients and Methods: We searched the electronic medical records at our tertiary referral center for episodes of cholangitis in patients with ADPKD or ADPLD from January 1, 1996, through June 30, 2017. Cases were categorized as suspected or definite cholangitis by expert review. Clinical, laboratory, and radiologic data were manually abstracted. A nested case-control study was conducted to investigate risk factors for cholangitis in patients with ADPKD. Results: We identified 29 cases of definite or suspected cholangitis complicating PLD (24 with ADPKD-associated PLD and 5 with ADPLD). Among patients with definite cholangitis in ADPKD-associated PLD (n=19) vs ADPLD (n=4), the mean ± SD age was 62.4±12.2 vs 55.1±8.6 years, and 9 (47.4%) vs 0 (0%), respectively, were male. The odds of gallstones (odds ratio [OR], 21.6; 95% CI, 3.17-927; P

BACKGROUND: Use of electronic health records (EHRs) in health research may lead to the false assumption of complete event ascertainment. We present a systematic approach to estimate “observation windows” (OWs), defined as time periods within which the assumption of complete ascertainment of events is more likely to hold, as a quality control approach to reducing the likelihood of this false assumption. We demonstrate the impact of observation windows on estimating the rates of type 2 diabetes mellitus (diabetes) using EHR diagnosis, medication, and laboratory data from HIV clinical cohorts. METHODS: Data contributed by 16 HIV clinical cohorts to the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) were used to identify and evaluate OWs for an operationalized definition of diabetes occurrence as a case study. Procedures included: 1) gathering cohort-level data; 2) visualizing and summarizing gaps in observations; 3) systematically establishing start and stop dates during which complete ascertainment of diabetes events was reasonable; and 4) visualizing the diabetes OWs relative to the cohort open and close dates to identify periods of time during which immortal person time was accumulated and events were not fully ascertained. We estimated diabetes occurrence event rates and 95% confidence intervals ([,]) in the most recent decade that data were available (Jan 1, 2007 to Dec 31, 2016). RESULTS: The number of diabetes events decreased by 17% with the use of the diabetes OWs; immortal person-time was removed decreasing total person-years by 23%. Consequently, the diabetes rate increased from 1.23 (95% confidence interval [1.20, 1.25]) per 100 person-years to 1.32 ([1.29, 1.35] per 100 person-years with the use of diabetes OWs. CONCLUSIONS: As the use of EHR-curated data for event-driven health research continues to expand, OWs have utility as a quality control approach to complete event ascertainment, helping to improve accuracy of estimates by removing immortal person-time when ascertainment is incomplete.

Crystalglobulinemia, a rare manifestation of monoclonal gammopathy, results from vascular deposition of crystallized monoclonal proteins leading to tissue injury. A 56-year-old man initially presented several years earlier with migratory polyarthralgias and blurry vision with no unifying diagnosis. Following an acute episode of malignant hypertension and rapidly progressive kidney failure, kidney biopsy was performed and was interpreted as idiopathic thrombotic microangiopathy. Further evaluation revealed an underlying monoclonal protein disorder. Slit-lamp biomicroscopy evaluation showed crystalline keratopathy. Re-evaluation of the kidney biopsy material with pronase staining confirmed crystalglobulin-induced nephropathy. The patient was initially treated with cyclophosphamide, bortezomib, and dexamethasone with partial response, followed by autologous stem cell transplantation with normalization of monoclonal protein studies, improvement in kidney function and joint symptoms, and decreased corneal deposits. His disease recurred but did not require additional treatment 1 year later. This case exemplifies the unique systemic presentation of diseases in the monoclonal gammopathy spectrum and emphasizes the need for a multidisciplinary approach when caring for these patients. Index Words: Crystalglobulin nephropathy, crystalglobulinemia, crystalline keratopathy

Objectives To determine and compare the rates of progress made by pre-school aged children with all degrees and types of hearing impairment and deafness, both with and without additional needs as catalogued using SNOMED CT, at the end of a non-statutory programme of individualised Auditory Verbal (AV) intervention. Methods An audit was conducted using a retrospective and comparative study design to examine spoken language outcomes in children who had spent more than two years on an AV programme and had completed their programmes between January 2007 and December 2017. The children were stratified according to i) whether they achieved age appropriate language (AAL) (n =102) or not (n =27); ii) whether they had deafness alone (n = 77) or deafness with additional needs (n =52); and iii) whether children with additional needs achieved AAL (n= 27) or not (n =25). Children undertook standardised spoken language assessments on joining the AV programme and then at intervals of at least 6 months for the duration of their programme. Derived measures of rates of language development (RLD) were used to compare the groups at i) the outset (initial RLD), and ii) the conclusion of the AV programme (programme RLD). Results Overall, 79% of children within this cohort achieved age appropriate spoken language scores. Children with additional needs (40%) embarked on a non-statutory AV programme at a significantly older age (corrected for prematurity), with significantly lower initial RLD and, as a group, attained significantly lower programme RLD compared with children with deafness alone. One in two of the children with additional needs reached AAL by the end of their individualised programme. The children with additional needs also demonstrated a highly significant increase in their mean programme RLD compared with the mean initial RLD indicating an acceleration in acquiring spoken language competencies while on the AV programme. Conclusions For deaf children with additional needs who stay on an AV programme for more than two years, listening and spoken communication is significantly enhanced. Specific access to the AV approach in addition to generic, statutory early intervention could facilitate deaf children with additional needs to achieve or approach AAL. Ensuring families have access to effective early intervention increases the chances that i) a suitable communication approach is adopted at the earliest opportunity, and ii) a child with additional needs acquires listening and spoken language at a rate commensurate with their full potential. Applying the SNOMED CT framework as a means of categorising children’s additional needs will enable more effective comparisons across studies from different centres around the world.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of numerous renal cysts leading to kidney enlargement and chronic kidney disease. Extra-renal manifestations, including polycystic liver disease and connective tissue defects, are frequently observed in ADPKD. Acute cyst complications, i.e. hemorrhage and infection, represent rare but severe conditions of ADPKD. The distinction between cystic versus non-cystic abdominal complications is often problematic. Here, we propose a practical guide for the diagnostic and therapeutic management of an "acute abdominal pain with fever" in patients with ADPKD.

ObjectivesInforming research participants of the results of studies in which they took part is viewed as an ethical imperative. However, there is little guidance in the literature about how to do this. The Fluoxetine Or Control Under Supervision trial randomised 3127 patients with a recent acute stroke to 6 months of fluoxetine or placebo and was published in the Lancet on 5 December 2018. The trial team decided to inform the participants of the results at exactly the same time as the Lancet publication, and also whether they had been allocated fluoxetine or placebo. In this report, we describe how we informed participants of the results.DesignIn the 6-month and 12-month follow-up questionnaires, we invited participants to provide an email address if they wished to be informed of the results of the trial. We re-opened our trial telephone helpline between 5 December 2018 and 31 March 2019.SettingUK stroke services.Participants3127 participants were randomised. 2847 returned 6-month follow-up forms and 2703 returned 12-month follow-up forms; the remaining participants had died (380), withdrawn consent or did not respond.ResultsOf those returning follow-up questionnaires, a total of 1845 email addresses were provided and a further 50 people requested results to be sent by post. Results were sent to all email and postal addresses provided; 309 emails were returned unrecognised. Seventeen people replied, of whom three called the helpline and the rest responded by email.ConclusionIt is feasible to disseminate results of large trials to research participants, though only around 60% of those randomised wanted to receive the results. The system we developed was efficient and required very little resource, and could be replicated by trialists in the future.Trial registration numberISRCTN83290762; Post-results.

From 2005 to 2018, among 32013 adults with human immunodeficiency virus entering care, median time to antiretroviral therapy (ART) prescription declined from 69 to 6 days, CD4 count at entry into care increased from 300 to 362 cells/μL, and CD4 count at ART prescription increased from 160 to 364 cells/μL.

BACKGROUND AND OBJECTIVES: We assessed safety and efficacy of another somatostatin receptor analog, pasireotide long-acting release, in severe polycystic liver disease and autosomal dominant polycystic kidney disease. Pasireotide long-acting release, with its broader binding profile and higher affinity to known somatostatin receptors, has potential for greater efficacy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Individuals with severe polycystic liver disease were assigned in a 2:1 ratio in a 1-year, double-blind, randomized trial to receive pasireotide long-acting release or placebo. Primary outcome was change in total liver volume; secondary outcomes were change in total kidney volume, eGFR, and quality of life. RESULTS: Of 48 subjects randomized, 41 completed total liver volume measurements (n=29 pasireotide long-acting release and n=12 placebo). From baseline, there were −99±189 ml/m absolute and −3%±7% change in annualized change in height-adjusted total liver volume (from 2582±1381 to 2479±1317 ml/m) in the pasireotide long-acting release group compared with 136±117 ml/m absolute and 6%±7% increase (from 2387±759 to 2533±770 ml/m) in placebo (P

Background Persons with human immunodeficiency virus (PWH) with persistently low CD4 counts despite efficacious antiretroviral therapy could have higher hospitalization risk. Methods In 6 US and Canadian clinical cohorts, PWH with virologic suppression for ≥1 year in 2005–2015 were followed until virologic failure, loss to follow-up, death, or study end. Stratified by early (years 2–5) and long-term (years 6–11) suppression and lowest presuppression CD4 count Results The 6997 included patients (19 980 person-years) were 81% cisgender men and 40% white. Among patients with lowest presuppression CD4 count 500 cells/μL had aIRRs of 1.44 during early suppression (95% confidence interval [CI], 1.01–2.06), and 1.67 (95% CI, 1.03–2.72) during long-term suppression. Among patients with lowest presuppression CD4 count ≥200 (56%), patients with current CD4 351–500 vs >500 cells/μL had an aIRR of 1.22 (95% CI, .93–1.60) during early suppression and 2.09 (95% CI, 1.18–3.70) during long-term suppression. Conclusions Virologically suppressed patients with lower CD4 counts experienced higher hospitalization rates and could potentially benefit from targeted clinical management strategies.

PurposeTo determine sources of variation between countries in per-capita mortality from COVID-19 (caused by the SARS-CoV-2 virus).MethodsPotential predictors of per-capita coronavirus-related mortality in 200 countries by May 9, 2020 were examined, including age, sex, obesity prevalence, temperature, urbanization, smoking, duration of infection, lockdowns, viral testing, contact tracing policies, and public mask-wearing norms and policies. Multivariable linear regression analysis was performed.ResultsIn univariate analyses, the prevalence of smoking, per-capita gross domestic product, urbanization, and colder average country temperature were positively associated with coronavirus-related mortality. In a multivariable analysis of 196 countries, the duration of infection in the country, and the proportion of the population 60 years of age or older were positively associated with per-capita mortality, while duration of mask-wearing by the public was negatively associated with mortality (all pConclusionsSocietal norms and government policies supporting the wearing of masks by the public, as well as international travel controls, are independently associated with lower per-capita mortality from COVID-19.

Polycystic liver disease can cause severe symptomatic hepatomegaly. Combined partial hepatectomy and cyst fenestration can be performed to reduce liver volume and symptom burden. We aimed to assess change in symptom relief and quality of life 6 months after partial hepatectomy and cyst fenestration in polycystic liver disease patients.We established a prospective cohort between 2014 and 2018 at a referral center in the United States. Patients who underwent partial hepatectomy and cyst fenestration for volume-related symptoms were included. Primary outcome was change in polycystic liver disease-related symptoms, measured with Polycystic Liver Disease Questionnaire. Secondary outcomes were change in liver volume (computed tomography/ magnetic resonance imaging) and change in quality of life, measured with the 12-Item Short Form Survey and the EuroQoL Visual Analogue Scale. Questionnaire scores range from 0 to 100 and were assessed before and 6 months after partial hepatectomy and cyst fenestration. Surgical complications were scored according to Clavien-Dindo (grade 1 to 5).We included 18 patients (mean age 52 years, 82% female). Partial hepatectomy and cyst fenestration reduced median liver volume (4,917 to 2,120 mL). Symptoms, measured with Polycystic Liver Disease Questionnaire, decreased (76.9 to 34.8 points; P.001) 6 months after surgery; 15/16 symptoms declined after treatment, with the most impact seen on early satiety and dyspnea. Quality of life also improved after surgery: median physical and mental component scales of the 12-Item Short Form Survey and EuroQoL Visual Analog Scale increased (24.9 to 45.7, P = .004; 40.5 to 55.4, P = .02; and 40.0 to 72.5, P = .003). Major complications (grade 4) occurred in 2 patients. There was no procedure-related mortality.Partial hepatectomy and cyst fenestration substantially improves symptom burden and quality of life in highly symptomatic polycystic liver disease patients.

Background Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS). Methods FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied. Results There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (−7.6 points, P = 0.02) and mobility (−4.2, P = 0.02), the number of reported symptoms was associated with worse depression (−2.7 per symptom, P = 0.009) and anxiety (−2.3, P = 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (−2.8 per visit, P Conclusions PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes.

International audience; Background and objectives The prevalence of autosomal dominant polycystic kidney disease (ADPKD) remains controversial. Incidence rates in Olmsted County, Minnesota, during 1935–1980 were previously reported. The current work extends this study to 2016. Design, setting, participants, & measurements The Rochester Epidemiology Project and radiology databases of Mayo Clinic and Olmsted Medical Center (healthcare providers for Olmsted County) were searched to identify all subjects meeting diagnostic criteria for definite, likely, and possible ADPKD. Annual incidence rates were calculated using incident cases during 1980–2016 as numerator and age- and sex-specific estimates of the population of Olmsted County as denominator. Point prevalence was calculated using prevalence cases as numerator and age- and sex-specific estimates of the population of Olmsted County on January 1, 2010 as denominator. Survival curves from the time of diagnosis were compared with expected survival of the Minnesota population. Results The age- and sex-adjusted annual incidence of definite and likely ADPKD diagnosis during 1980–2016 was 3.06 (95% CI, 2.52 to 3.60) per 100,000 person-years, which is 2.2 times higher than that previously reported for 1935–1980 (1.38 per 100,000 person-years). The point prevalence of definite or likely ADPKD on January 1, 2010 was 68 (95% CI, 53.90 to 82.13) per 100,000 population. Much higher incidence rates and point prevalence were obtained when possible ADPKD cases were included. Contrary to the previous Olmsted County study, patient survival in this study was not different from that in the general population. Conclusions The point prevalence of definite and likely ADPKD observed in this study is higher than those reported in the literature, but lower than genetic prevalence based on estimates of disease expectancy or on analysis of large population-sequencing databases.

Background People living with human immunodeficiency virus (HIV; PLWH) have a markedly elevated anal cancer risk, largely due to loss of immunoregulatory control of oncogenic human papillomavirus infection. To better understand anal cancer development and prevention, we determined whether recent, past, cumulative, or nadir/peak CD4+ T-cell count (CD4) and/or HIV-1 RNA level (HIV RNA) best predict anal cancer risk. Methods We studied 102 777 PLWH during 1996–2014 from 21 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. Using demographics-adjusted, cohort-stratified Cox models, we assessed associations between anal cancer risk and various time-updated CD4 and HIV RNA measures, including cumulative and nadir/peak measures during prespecified moving time windows. We compared models using the Akaike information criterion. Results Cumulative and nadir/peak CD4 or HIV RNA measures from approximately 8.5 to 4.5 years in the past were generally better predictors for anal cancer risk than their corresponding more recent measures. However, the best model included CD4 nadir (ie, the lowest CD4) from approximately 8.5 years to 6 months in the past (hazard ratio [HR] for Conclusions Our results are consistent with anal cancer promotion by severe, prolonged HIV-induced immunosuppression. Nadir and cumulative CD4 may represent useful markers for identifying PLWH at higher anal cancer risk.

Background Osteoporosis, an indicator of significant bone loss, has been consistently reported among older breast cancer survivors. Data are limited on the incidence of osteopenia, an earlier indicator of bone loss, and osteoporosis in younger breast cancer survivors compared with cancer-free women. Methods We prospectively examined bone loss in 211 breast cancer survivors (mean age at breast cancer diagnosis = 47 years) compared with 567 cancer-free women in the same cohort with familial risk for breast cancer. Multivariable-adjusted Cox proportional hazards models were used to estimate HRs and 95% CIs of osteopenia and/or osteoporosis incidence based on physician diagnosis. Results During a mean follow-up of 5.8 years, 66% of breast cancer survivors and 53% of cancer-free women reported having a bone density examination, and 112 incident cases of osteopenia and/or osteoporosis were identified. Breast cancer survivors had a 68% higher risk of osteopenia and osteoporosis compared to cancer-free women (HR = 1.68, 95% CI = 1.12–2.50). The association was stronger among recent survivors after only 2 years of follow-up (HR = 2.74, 95% CI = 1.37–5.47). A higher risk of osteopenia and osteoporosis was also observed among survivors aged ≤ 50 years, estrogen receptor-positive tumors, and those treated with aromatase inhibitors alone or chemotherapy plus any hormone therapy relative to cancer-free women. Conclusions Younger breast cancer survivors are at higher risk for osteopenia and osteoporosis compared to cancer-free women. Studies are needed to determine effective approaches to minimize bone loss in this population.

BACKGROUND AND OBJECTIVES: In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 and 1-year Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, tolvaptan slowed the decline of eGFR in patients with autosomal dominant polycystic kidney disease at early and later stages of CKD, respectively. Our objective was to ascertain whether the reduction associated with the administration of tolvaptan is sustained, cumulative, and likely to delay the need for kidney replacement therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: One hundred and twenty-eight patients with autosomal dominant polycystic kidney disease participated in clinical trials of tolvaptan at the Mayo Clinic. All had the opportunity to enroll into open-label extension studies. Twenty participated in short-term studies or received placebo only. The remaining 108 were analyzed for safety. Ninety seven patients treated with tolvaptan for ≥1 year (mean±SD, 4.6±2.8; range, 1.1–11.2) were analyzed for efficacy using three approaches: (1) comparison of eGFR slopes and outcome (33% reduction from baseline eGFR) to controls matched by sex, age, and baseline eGFR; (2) Stability of eGFR slopes with duration of follow-up; and (3) comparison of observed and predicted eGFRs at last follow-up. RESULTS: Patients treated with tolvaptan had lower eGFR slopes from baseline (mean±SD, −2.20±2.18 ml/min per 1.73 m(2) per year) and from month 1 (mean±SD, −1.97±2.44 ml/min per 1.73 m(2) per year) compared with controls (mean±SD, −3.50±2.09 ml/min per 1.73 m(2) per year; P

Background The HALT PKD trial in early autosomal dominant polycystic kidney disease (ADPKD) showed that intensive control of systolic blood pressure to 95-110 mmHg was associated with a 14% slower rate of kidney volume growth compared to standard control. It is unclear whether this result was due to greater blockade of the renin-angiotensin-aldosterone system (RAAS) by allowing the use of higher drug doses in the low blood pressure arm, or due to the lower blood pressure per se. Methods In this secondary analysis of HALT PKD Study A, we categorized participants into high and low dose groups based on the median daily equivalent dose of RAAS blocking drugs used after the initial dose titration period. Using linear mixed models, we compared the percent change in total kidney volume and the slope of estimated glomerular filtration rate (eGFR) between the 2 groups. We also assessed the effects of time-varying dose and time-varying blood pressure parameters on these outcomes. Results Subjects in the high dose group (n=252) did not experience a slower increase in total kidney volume than those in the low-dose (n=225) group, after adjustment for age, sex, genotype, and BP arm. The chronic slope of eGFR decline was similar in the 2 groups. Higher time-varying systolic blood pressure was associated with a steeper decline in eGFR. Conclusion ADPKD progression (as detected by eGFR decline and TKV increase) was ameliorated by intense blood pressure control as opposed to pharmacologic intensity of RAAS blockade.

Background Previous clinical studies of autosomal dominant polycystic kidney disease (ADPKD) reported that loss of kidney function usually follows a steep and relentless course. A detailed examination of individual patterns of decline in estimated glomerular filtration rate (eGFR) has not been performed. Study Design Longitudinal post hoc analysis of data collected during the Halt Progression of Polycystic Kidney Disease (HALT-PKD) trials. Setting & Participants 494 HALT-PKD Study A participants (younger; preserved eGFR) and 435 Study B participants (older; reduced eGFR) who had more than 3 years of follow-up and 7 or more eGFR assessments. Measurements Longitudinal eGFR assessments using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation. Predictors Demographic, clinical, laboratory, and imaging features of participants. Outcomes Probability of linear and nonlinear decline patterns or of stable eGFR calculated for each participant from a Bayesian model of individual eGFR trajectories. Results Most (62.5% in Study A and 81% in Study B) participants had a linear decline in eGFR during up to 8 years of follow-up. A proportion (22% in Study A and 13% in Study B) of progressors had a nonlinear pattern. 15.5% of participants in Study A and 6% in Study B had a prolonged (≥4.5 years) period of stable eGFRs. These individuals (Study A) had significantly smaller total kidney volumes, higher renal blood flows, lower urinary albumin excretion, and lower body mass index at baseline and study end. In Study B, participants with reduced but stable eGFRs were older than the progressors. Two-thirds of nonprogressors in both studies had PKD1 mutations, with enrichment for weak nontruncating mutations. Limitations Relatively short follow-up of a clinical trial population. Conclusions Although many individuals with ADPKD have a linear decline in eGFR, prolonged intervals of stable GFRs occur in a substantial fraction. Lower body mass index was associated with more stable kidney function in early ADPKD.

High-dose methotrexate has been a treatment for osteosarcoma; however, its nephrotoxic effects are considerable. Carboxypeptidase-G2 (glucarpidase) was approved by the US Food and Drug Administration in 2012 for treatment of toxic methotrexate levels. We report our experience using glucarpidase under compassionate use before Food and Drug Administration approval in 2 patients who had delayed methotrexate clearance and prolonged kidney injury despite glucarpidase administration. Our results show that patients with methotrexate toxicity may require repeated doses of glucarpidase in addition to supportive measures, such as dialysis.

Introduction Fibrillary glomerulonephritis (FGN) is a rare disease with unknown pathogenesis and a poor prognosis. Until now, the diagnosis of this disease has required demonstration of glomerular deposition of randomly oriented fibrils by electron microscopy that are Congo red negative and stain with antisera to Igs. We recently discovered a novel proteomic tissue biomarker for FGN, namely, DNAJB9. Methods In this work, we developed DNAJB9 immunohistochemistry and tested its sensitivity and specificity for the diagnosis of FGN. This testing was performed on renal biopsy samples from patients with FGN (n = 84), amyloidosis (n = 21), a wide variety of non-FGN glomerular diseases (n = 98), and healthy subjects (n = 11). We also performed immunoelectron microscopy to determine whether DNAJB9 is localized to FGN fibrils. Results Strong, homogeneous, smudgy DNAJB9 staining of glomerular deposits was seen in all but 2 cases of FGN. The 2 cases that did not stain for DNAJB9 were unique, as they had glomerular staining for IgG only (without κ or λ) on immunofluorescence. DNAJB9 staining was not observed in cases of amyloidosis, in healthy subjects, or in non-FGN glomerular diseases (with the exception of very focal staining in 1 case of smoking-related glomerulopathy), indicating 98% sensitivity and > 99% specificity. Immunoelectron microscopy showed localization of DNAJB9 to FGN fibrils but not to amyloid fibrils or immunotactoid glomerulopathy microtubules. Conclusion DNAJB9 immunohistochemistry is sensitive and specific for FGN. Incorporation of this novel immunohistochemical biomarker into clinical practice will now allow more rapid and accurate diagnosis of this disease.

In order to deliver equal healthcare access to resource-poor settings, sustainable, cost-effective systems of communication should be used. As mobile phone use increases, remote care can be delivered via teledermatology using Apps. This commentary covers how WhatsApp could be used by dermatologists seeking to deliver healthcare in this context.

Background Uncertainty underlies the effectiveness of somatostatin analogues for slowing the progression of polycystic kidney or liver disease. Methods Eligible studies included randomized controlled trials (RCTs) evaluating somatostatin analog as therapy for patients with polycystic kidney disease (PKD) or polycystic liver disease (PLD) compared to placebo or standard therapy. Two reviewers independently screened studies identified from databases (MEDLINE, EMBASE, Cochrane Database), clinical trial registries, and references from pertinent articles and clinical practice guidelines. Outcome measurements were changes in total liver volume (TLV), total kidney volume (TKV), and estimated glomerular filtration rate (eGFR). Results Of 264 nonduplicate studies screened, 10 RCTs met the inclusion criteria. The body of evidence provided estimates warranting moderate confidence. Meta-analysis of 7 RCTs including a total of 652 patients showed that somatostatin analogs are associated with a lower %TLV growth rate compared to control (mean difference, -6.37%; 95% CI -7.90 to -4.84, p.00001), and with a lower %TKV growth rate compared to control (mean difference, -3.66%; 95% CI -5.35 to -1.97, p.0001). However, it was not associated with a difference in eGFR decline (mean difference, -0.96 mL/min./1.73m2; 95% CI -2.38 to 0.46, p = 0.19). Conclusions Current body of evidence suggests that somatostatin analogs therapy slows the increase rate of TLV and TKV in patients with PKD or PLD compared to control within a 3-year follow-up period. It does not seem to have an effect on the change in eGFR. Somatostatin analogs therapy can be a promising treatment for ADPKD or ADPLD, and we need to continue to research its effectiveness for ADPKD or ADPLD.

The association of overweight/obesity with disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) remains untested. We hypothesized that overweight/obesity associates with faster progression in early-stage ADPKD. Overall, 441 nondiabetic participants with ADPKD and an eGFR>60 ml/min per 1.73 m2 who participated in the Halt Progression of Polycystic Kidney Disease Study A were categorized on the basis of body mass index (BMI; calculated using nonkidney and nonliver weight) as normal weight (18.5–24.9 kg/m2; reference; n=192), overweight (25.0–29.9 kg/m2; n=168), or obese (≥30 kg/m2; n=81). We evaluated the longitudinal (5-year) association of overweight/obesity with change in total kidney volume (TKV) by magnetic resonance imaging using linear regression and multinomial logistic regression models. Among participants, mean±SD age was 37±8 years, annual percent change in TKV was 7.4%±5.1%, and BMI was 26.3±4.9 kg/m2. The annual percent change in TKV increased with increasing BMI category (normal weight: 6.1%±4.7%, overweight: 7.9%±4.8%, obese: 9.4%±6.2%; P

Introduction Mutations in PKD1 and PKD2 cause autosomal dominant polycystic kidney disease (ADPKD). Experimental evidence suggests an important role of the polycystins in cardiac development and myocardial function. To determine whether ADPKD may predispose to the development of cardiomyopathy, we have evaluated the coexistence of diagnoses of ADPKD and primary cardiomyopathy in our patients. Methods Clinical data were retrieved from medical records for patients with a coexisting diagnosis of ADPKD and cardiomyopathies evaluated at the Mayo Clinic (1984–2015). Results Among the 58 of 667 patients with available echocardiography data, 39 (5.8%) had idiopathic dilated cardiomyopathy (IDCM), 17 (2.5%) had hypertrophic obstructive cardiomyopathy, and 2 (0.3%) had left ventricular noncompaction. Genetic data were available for 19, 8, and 2 cases of IDCM, hypertrophic obstructive cardiomyopathy, and left ventricular noncompaction, respectively. PKD1 mutations were detected in 42.1%, 62.5%, and 100% of IDCM, hypertrophic obstructive cardiomyopathy, and left ventricular noncompaction cases, respectively. PKD2 mutations were detected only in IDCM cases and were overrepresented (36.8%) relative to the expected frequency in ADPKD (15%). In at least 1 patient from 3 IDMC families and 1 patient from a hypertrophic obstructive cardiomyopathy family, the cardiomyopathy did not segregate with ADPKD, suggesting that the PKD mutations may be predisposing factors rather than solely responsible for the development of cardiomyopathy. Discussion Coexistence of ADPKD and cardiomyopathy in our tertiary referral center cohort appears to be higher than expected by chance. We suggest that PKD1 and PKD2 mutations may predispose to primary cardiomyopathies and that genetic interactions may account for the observed coexistence of ADPKD and cardiomyopathies.

The CRISP study of polycystic kidney disease (PKD) found that urinary sodium excretion associated with the rate of total kidney volume increase. Whether sodium restriction slows the progression of Autosomal Dominant PKD (ADPKD) is not known. To evaluate this we conducted a post hoc analysis of the HALT-PKD clinical trials of renin-angiotensin blockade in patients with ADPKD. Linear mixed models examined whether dietary sodium affected rates of total kidney volume or change in estimated glomerular filtration rate (eGFR) in patients with an eGFR over 60 ml/min/1.73 m 2 (Study A) or the risk for a composite endpoint of 50% reduction in eGFR, end-stage renal disease or death, or the rate of eGFR decline in patients with an eGFR 25–60 ml/min/1.73 m 2 (Study B) all in patients initiated on an under100 mEq sodium diet. During the trial urinary sodium excretion significantly declined by an average of 0.25 and 0.41 mEq/24 hour per month in studies A and B, respectively. In Study A, averaged and time varying urinary sodium excretions were significantly associated with kidney growth (0.43%/year and 0.09%/year, respectively, for each 18 mEq urinary sodium excretion). Averaged urinary sodium excretion was not significantly associated with faster eGFR decline (–0.07 ml/min/1.73m 2 /year for each 18 mEq urinary sodium excretion). In Study B, the averaged but not time-varying urinary sodium excretion significantly associated with increased risk for the composite endpoint (hazard ratio 1.08 for each 18 mEq urinary sodium excretion) and a significantly faster eGFR decline (–0.09 ml/min/1.73m 2 /year for each mEq 18 mEq urinary sodium excretion). Thus, sodium restriction is beneficial in the management of ADPKD.

Introduction Alport syndrome (AS) is a genetic disorder characterized by progressive hematuric nephropathy with or without sensorineural hearing loss and ocular lesions. Previous studies on AS included mostly children. Methods To determine the prognostic value of loss of staining for collagen type IV alpha 5 (COL4A5) and its relationship with the ultrastructural glomerular basement membrane alterations, we performed direct immunofluorescence using a mixture of fluorescein isothiocyanate-conjugated and Texas-red conjugated antibodies against COL4A5 and COL4A2, respectively, on renal biopsies of 25 males with AS (including 16 who were diagnosed in adulthood). Results All patients showed normal positive staining of glomerular basement membranes and tubular basement membranes for COL4A2. Of the 25 patients, 10 (40%) patients showed loss of staining for COL4A5 (including 89% of children and 13% of adults) and the remaining 15 (60%) had intact staining for COL4A5. Compared with patients with intact staining for COL4A5, those with loss of staining had more prominent ultrastructural glomerular basement membrane alterations and were younger at the time of biopsy. By Kaplan-Meier survival analysis and Cox regression analysis, loss of staining for COL4A5 predicted earlier progression to overt proteinuria and stage 2 chronic kidney disease or worse. By multivariate Cox regression analysis, loss of staining for COL4A5 was an independent predictor of the development of overt proteinuria and stage 2 chronic kidney disease or worse. Discussion Thus, the COL4A5 expression pattern has an important prognostic value and it correlates with the severity of ultrastructural glomerular basement membrane alterations in males with AS. Loss of COL4A5 staining is uncommon in patients with AS diagnosed in their adulthood.

Objectives Pancreatic lesions in autosomal dominant polycystic kidney disease (ADPKD) are primarily cysts. They are increasingly recognized, with isolated reports of intraductal papillary mucinous neoplasia (IPMN). Methods Retrospective study to determine prevalence, number, size, and location of pancreatic abnormalities using abdominal magnetic resonance imaging (MRI) of genotyped ADPKD patients (seen February 1998 to October 2013) and compared with age- and sex-matched non-ADPKD controls. We evaluated presentation, investigation, and management of all IPMNs among individuals with ADPKD (January 1997 to December 2016). Results Abdominal MRIs were examined for 271 genotyped ADPKD patients. A pancreatic cyst lesion (PCL) was detected in 52 patients (19%; 95% confidence interval, 15%-23%). Thirty-seven (71%) had a solitary PCL; 15 (28%) had multiple. Pancreatic cyst lesion prevalence did not differ by genotype. Intraductal papillary mucinous neoplasia was detected in 1% of ADPKD cases. Among 12 IPMN patients (7 branch duct; 5 main duct or mixed type) monitored for about 140 months, 2 with main duct IPMNs required Whipple resection, and 1 patient died of complications from small-bowel obstruction after declining surgical intervention. Conclusions With MRI, PCLs were detected in 19% and IPMNs in 1% of 271 ADPKD patients with proven mutations, without difference across genotypes. Pancreatic cyst lesions were asymptomatic and remained stable in size.

BackgroundResearch is needed to better understand relations between immunosuppression and HIV viraemia and risk for non-Hodgkin lymphoma, a common cancer in people living with HIV. We aimed to identify key CD4 count and HIV RNA (viral load) predictors of risk for non-Hodgkin lymphoma, overall and by subtype.MethodsWe studied people living with HIV during 1996-2014 from 21 Canadian and US cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. To determine key independent predictors of risk for non-Hodgkin lymphoma, we assessed associations with time-updated recent, past, cumulative, and nadir or peak measures of CD4 count and viral load, using demographics-adjusted, cohort-stratified Cox models, and we compared models using Akaike's information criterion.FindingsOf 102 131 people living with HIV during the study period, 712 people developed non-Hodgkin lymphoma. The key independent predictors of risk for overall non-Hodgkin lymphoma were recent CD4 count (ie, lagged by 6 months

Background: High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset.Methods: We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UK-based ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053.Findings: Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in the sham group). The median time to randomisation was 71 min (IQR 45–116). 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at the final diagnosis of the index event. In the GTN group, participants' systolic blood pressure was lowered by 5·8 mm Hg compared with the sham group (pvs 3 [2–5]; n=558, in the sham group; 1·04 [0·84–1·29]; p=0·69). We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs 170 in the sham group [p=0·16]) between treatment groups.Interpretation: Prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultra-acute prehospital setting.Funding: British Heart Foundation.

The presence of KMT2A/AFF1 rearrangement in B-lymphoblastic leukemia (B-ALL) is an independent poor prognostic factor and has been associated with higher rate of treatment failure and higher risk of linage switch under therapy. Blinatumomab has shown promising therapeutic results in refractory or relapsed B-ALL; however, it has potential risk of inducing lineage switch, especially in KMT2A/AFF1 rearranged B-ALL into acute myeloid leukemia and/or myeloid sarcoma. We report a 40-year-old female with KMT2A/AFF1-rearranged B-ALL that was refractory to conventional chemotherapy. Following administration of blinatumomab, she developed a breast mass proven to be myeloid sarcoma, in addition to bone marrow involvement by AML. Approximately six weeks after cessation of blinatumomab, a repeat bone marrow examination revealed B/myeloid MPAL.

BACKGROUND AND OBJECTIVES: Intracranial aneurysm rupture is the most devastating complication of autosomal dominant polycystic kidney disease. Whether selective or widespread intracranial aneurysm screening is indicated remains controversial. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Records of 3010 patients with autosomal dominant polycystic kidney disease evaluated at the Mayo Clinic between 1989 and 2017 were reviewed. Those who had presymptomatic magnetic resonance angiography screening were included. RESULTS: Ninety-four intracranial aneurysms were diagnosed in 75 of 812 (9%) patients who underwent magnetic resonance angiography screening. Sex, age, race, and genotype were similar in the groups with and without aneurysms; hypertension and history of smoking were more frequent in the aneurysm group. Twenty-nine percent of patients with aneurysms compared with 11% of those without aneurysms had a family history of subarachnoid hemorrhage (P

IgA nephropathy frequently leads to progressive CKD. Although interest surrounds use of immunosuppressive agents added to standard therapy, several recent studies have questioned efficacy of these agents. Depleting antibody–producing B cells potentially offers a new therapy. In this open label, multicenter study conducted over 1-year follow-up, we randomized 34 adult patients with biopsy–proven IgA nephropathy and proteinuria >1 g/d, maintained on angiotensin–converting enzyme inhibitors or angiotensin receptor blockers with well controlled BP and eGFR

Random urine protein creatinine ratios are used to estimate 24-hour urine protein excretion, which is considered a diagnostic gold standard. However, few studies are available of the sensitivity and specificity of this estimation in patients with glomerular proteinuria. To clarify this, we measured the urine protein and creatinine centrally in random and 24-hour urine collections at biopsy and longitudinally every 6 months in individuals participating in the Nephrotic Syndrome Study Network (NEPTUNE) cohort with glomerular disease. In the initial developmental cohort, 302 patients had same day random and 24-hour samples with a total of 827 paired measurements across all visits. The protein excretion (g/day) was higher in adult than pediatric patients. The correlation between the random urine protein creatinine ratio and 24-hour urine protein excretion was moderate in both groups (r of 0.60 and 0.67, respectively). However, the log 10 transformation of values strengthened correlations in both groups (r of 0.85 and 0.82, respectively). Associations were moderately stronger among obese patients. Prediction equations were developed and validated in 232 unique cases from NEPTUNE (R 2 of 0.65). Thus, in patients with glomerular disease and proteinuria, the urine protein creatinine ratio correlates only moderately with 24-hour urine protein excretion. However an estimating equation was developed to derive 24-hour urine protein excretion from random urine protein creatinine ratio values with improved precision. The long-term prognostic value of log 10 -transformed random protein creatinine ratios values requires future study.

Introduction Peripherally inserted central venous catheters (PICCs) may adversely impact future successful arteriovenous fistulae (AVF). As part of a quality improvement project, the performance of tunneled small bore tunneled central venous catheters (TSB-CVCs), as alternatives to PICCs, was evaluated. Methods A retrospective observational study, involving individuals ≥18 years of age who underwent TSB-CVC placement by Interventional Radiology at Mayo Clinic, Rochester, MN between 1/1/2010 and 8/30/2013. Findings The study cohort included 92 patients with a median age of 55 (46–67) years, who underwent 108 TSB-CVC placements. Baseline renal disease was present in 71% (77/108). Most TSB-CVCs were placed in hospitalized patients (94%; 102/108); five French in diameter (61%; 66/108) and located in an internal jugular vein (84%; 91/108). Median catheter indwelling time was 20 (11–43) days (n = 84). TSB-CVC-related bloodstream infection, deep venous thrombosis (DVT), and superficial venous thrombosis (SpVT) rates per line were 0.009 (1/108), 0.018 (2/108), and 0.009 (1/108), respectively. Venous outcomes in a subgroup of 54 patients, who had documented PICC placements (n = 161) in addition to TSB-CVC (n = 58) were compared. TSB-CVC-DVT rate was lower than the PICC-DVT rate (0.017 [1/58] vs. 0.106 per line [17/161]; P = 0.04). The TSB-CVC-SpVT rate was not different from the PICC-SpVT rate (0 [0/58] vs. 0.037 [6/161] per line; P = 0.14). Discussion TSB-CVCs demonstrated an excellent safety profile in our study. These catheters should be preferentially utilized for arm vein preservation in advanced kidney disease. Their impact on future AVF success needs further evaluation.

Item does not contain fulltext BACKGROUND & AIMS: Somatostatin analogues reduce liver volumes in polycystic liver disease. However, patients show considerable variability in treatment responses. Our aim was to identify specific patient, disease or treatment characteristics that predict response in polycystic liver disease during somatostatin analogue therapy. METHODS: We pooled the individual patient data of four trials that evaluated long-acting somatostatin analogues (120 mg lanreotide or 40 mg octreotide) for 6-12 months in polycystic liver disease patients. We performed uni- and multivariate linear regression analysis with preselected patient, disease and drug variables to identify independent predictors of response, defined as per cent change in liver or kidney volume (in ADPKD subgroup). All analyses were adjusted for baseline liver volume and centre. RESULTS: We included 153 polycystic liver disease patients (86% female, median liver volume 4974 ml) from three international centres, all treated with octreotide (n = 70) or lanreotide (n = 83). Mean reduction in liver volume was 4.4% (range -31.6 to +9.4%). Multivariate linear regression revealed that elevated baseline alkaline phosphatase was associated with increased liver volume reduction during therapy (-2.7%, 95% CI -5.1 to -0.2%, P = 0.04), independently of baseline liver volume. Somatostatin analogue type, underlying diagnosis and eGFR did not affect response. In our ADPKD subpopulation (n = 100), elevated alkaline phosphatase predicted liver volume reduction (-3.2%, P = 0.03) but did not predict kidney volume reduction (+0.1%, P = 0.97). Total gastro-intestinal symptom severity decreased with therapy in a subgroup analysis (n = 95; P < 0.001). CONCLUSION: Alkaline phosphatase is a liver-specific, independent predictor of response in polycystic liver disease during somatostatin analogue therapy.

Background and objectives This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and factors associated with complete proteinuria remission (CRever). Design, setting, participants, & measurements We enrolled adults and children with proteinuria ≥0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC)

Transfusion safety coordinators (TSCs) are an integral part of the transfusion process, which involves many interlinking chains of events and a multidisciplinary group of health professionals. In Australia, individual hospital-based TSCs have been in place for several decades, with state-based collaboratives commencing in 2002. The role has expanded across the country and currently there are 113 dedicated TSC positions and many more staff involved as blood/transfusion champions. There are also 12 transfusion nurse (TN) positions within the Australian Red Cross Blood Service. Over time both TSC and TN roles have evolved to meet the changes within the Australian blood sector. The primary focus of safety and appropriateness has now evolved to be more patient-centred by incorporating patient blood management (PBM) initiatives. National PBM guidelines, statements, strategies, criteria and healthcare standards specifically focused on all aspects of transfusion have influenced this evolution. TSCs undertake diverse roles and activities that vary significantly between health services and within each jurisdiction. Effective communication and change management skills are integral to the success of the role. Conclusion: The TSCs are highly recognised within the transfusion team and the role continues to evolve with the changes in the Australian blood sector. The term Transfusion Safety Coordinators (TSCs) has been used to describe roles such as transfusion nurse/trainer/practitioner/safety officer/clinical nurse consultant and PBM nurses.