Polycystic kidney diseases (PKDs) comprise the most common Mendelian forms of renal disease. It is characterised by the development of fluid-filled renal cysts, causing progressive loss of kidney ...function, culminating in the need for renal replacement therapy or kidney transplant. Ireland represents a valuable region for the genetic study of PKD, as family sizes are traditionally large and the population relatively homogenous. Studying a cohort of 169 patients, we describe the genetic landscape of PKD in Ireland for the first time, compare the clinical features of patients with and without a molecular diagnosis and correlate disease severity with autosomal dominant pathogenic variant type. Using a combination of molecular genetic tools, including targeted next-generation sequencing, we report diagnostic rates of 71-83% in Irish PKD patients, depending on which variant classification guidelines are used (ACMG or Mayo clinic respectively). We have catalogued a spectrum of Irish autosomal dominant PKD pathogenic variants including 36 novel variants. We illustrate how apparently unrelated individuals carrying the same autosomal dominant pathogenic variant are highly likely to have inherited that variant from a common ancestor. We highlight issues surrounding the implementation of the ACMG guidelines for variant pathogenicity interpretation in PKD, which have important implications for clinical genetics.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Introduction
Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of chronic kidney disease (CKD) and end‐stage renal disease (ESRD). We aimed to compare renal ...transplant outcomes in people with ESRD due to ADTKD to those with other causes of renal failure.
Methods
Patients with clinical characteristics consistent with ADTKD by the criteria outlined in the 2015 KDIGO consensus were included. We compared ADTKD transplant outcomes with those of 4633 non‐ADTKD renal transplant recipients.
Results
We included 31 patients who met diagnostic criteria for ADTKD in this analysis, 23 of whom had an identified mutation (28 were categorized as definite‐ADTKD and 3 as suspected ADTKD). Five patients received a second transplant during follow‐up. In total, 36 grafts were included. We did not identify significant differences between groups in terms of graft or patient survival after transplantation. Twenty‐five transplant biopsies were performed during follow‐up, and none of these showed signs of recurrent ADTKD post‐transplant.
Conclusion
In patients with ESRD due to ADTKD, we demonstrate that transplant outcomes are comparable with the general transplant population. There is no evidence that ADTKD can recur after transplantation.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less ...extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37%). A monogenic cause was identified in 36% of affected families with a positive family history of CKD, 69% of those with extra-renal features, and only 15% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40%), corrected the clinical diagnosis in 9 (22%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Solid organ transplant recipients are recognized to carry a high burden of malignancy and frequently this cancer develops in the head and neck region. Furthermore, cancer of the head and neck ...post-transplant carries a significantly increased mortality. In this study, we aim to conduct a national retrospective cohort study to investigate the impact of head and neck cancer in terms of frequency and mortality in a large group of solid organ transplant recipients over a 20 year time span and compare the mortality in transplant patients to non-transplant patients with head and neck cancer.
Patients in the Republic of Ireland who underwent solid organ transplantation between 1994 and 2014 who developed post-transplant head and neck malignancy were identified from the records of two prospective, national databases (National Cancer Registry of Ireland (NCRI) and The Irish Transplant Cancer Group database) working in conjunction with each other. Incidence of head and neck malignancy post-transplant was compared with the general population by means of standardised incidence ratios (SIR). Cumulative incidence of all cause and cancer related mortality from head and neck keratinocytic was undertaken by a competing risks analysis.
A total of 3346 solid organ transplant recipients were identified, 2382 (71.2 %) kidney, 562 (16.8 %) liver, 214 (6.4 %) cardiac and 188 (5.6 %) lung. During the period of follow up of 428 patients developed head and neck cancer, representing (12.8 %) of the population. 97 % of these patients developed keratinocytic cancers, specifically, of head and neck. The frequency of post-transplant head and neck cancer was related to the duration of immunosuppression with 14 % of patients developing cancer at 10 years and 20 % having developed at least one cancer by 15 years. 12 (3 %) patients developed non-cutaneous head and neck malignancy. 10 (0.3 %) patients died due to head and neck keratinocytic malignancy post-transplant. Competing risk analysis demonstrated that organ transplantation conferred a strong independent effect of death, compared to non-transplant patients with head and neck keratinocytes. This applied specifically for kidney (HR 4.4, 95 % CI 2.5–7.8) and heart transplants (HR 6.5, 95 % CI 2.1–19.9), and overall, across the four transplant categories (P < 0.001). The SIR of developing keratinocyte cancer varied based on primary tumor site, gender, and type of transplant organ.
Transplant patients demonstrate a particularly high rate of head and neck keratinocyte cancer with a very high rate of associated mortality. Physicians should be cognizant of the increased rate of malignancy in this population and monitor for red flag signs/symptoms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
IMPORTANCE Prevention strategies for heart failure are needed. OBJECTIVE To determine the efficacy of a screening program using brain-type natriuretic peptide (BNP) and collaborative care in an ...at-risk population in reducing newly diagnosed heart failure and prevalence of significant left ventricular (LV) systolic and/or diastolic dysfunction. DESIGN, SETTING, AND PARTICIPANTS The St Vincent’s Screening to Prevent Heart Failure Study, a parallel-group randomized trial involving 1374 participants with cardiovascular risk factors (mean age, 64.8 SD, 10.2 years) recruited from 39 primary care practices in Ireland between January 2005 and December 2009 and followed up until December 2011 (mean follow-up, 4.2 SD, 1.2 years). INTERVENTION Patients were randomly assigned to receive usual primary care (control condition; n=677) or screening with BNP testing (n=697). Intervention-group participants with BNP levels of 50 pg/mL or higher underwent echocardiography and collaborative care between their primary care physician and specialist cardiovascular service. MAIN OUTCOMES AND MEASURES The primary end point was prevalence of asymptomatic LV dysfunction with or without newly diagnosed heart failure. Secondary end points included emergency hospitalization for arrhythmia, transient ischemic attack, stroke, myocardial infarction, peripheral or pulmonary thrombosis/embolus, or heart failure. RESULTS A total of 263 patients (41.6%) in the intervention group had at least 1 BNP reading of 50 pg/mL or higher. The intervention group underwent more cardiovascular investigations (control, 496 per 1000 patient-years vs intervention, 850 per 1000 patient-years; incidence rate ratio, 1.71; 95% CI, 1.61-1.83; P<.001) and received more renin-angiotensin-aldosterone system–based therapy at follow-up (control, 49.6%; intervention, 56.5%; P=.01). The primary end point of LV dysfunction with or without heart failure was met in 59 (8.7%) of 677 in the control group and 37 (5.3%) of 697 in the intervention group (odds ratio OR, 0.55; 95% CI, 0.37-0.82; P = .003). Asymptomatic LV dysfunction was found in 45 (6.6%) of 677 control-group patients and 30 (4.3%) of 697 intervention-group patients (OR, 0.57; 95% CI, 0.37-0.88; P = .01). Heart failure occurred in 14 (2.1%) of 677 control-group patients and 7 (1.0%) of 697 intervention-group patients (OR, 0.48; 95% CI, 0.20-1.20; P = .12). The incidence rates of emergency hospitalization for major cardiovascular events were 40.4 per 1000 patient-years in the control group vs 22.3 per 1000 patient-years in the intervention group (incidence rate ratio, 0.60; 95% CI, 0.45-0.81; P = .002). CONCLUSION AND RELEVANCE Among patients at risk of heart failure, BNP-based screening and collaborative care reduced the combined rates of LV systolic dysfunction, diastolic dysfunction, and heart failure. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00921960
Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how ...blood-brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog. Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Type 1 diabetes affects over nine million individuals globally, with approximately 40% developing diabetic kidney disease. Emerging evidence suggests that epigenetic alterations, such as DNA ...methylation, are involved in diabetic kidney disease. Here we assess differences in blood-derived genome-wide DNA methylation associated with diabetic kidney disease in 1304 carefully characterised individuals with type 1 diabetes and known renal status from two cohorts in the United Kingdom-Republic of Ireland and Finland. In the meta-analysis, we identify 32 differentially methylated CpGs in diabetic kidney disease in type 1 diabetes, 18 of which are located within genes differentially expressed in kidneys or correlated with pathological traits in diabetic kidney disease. We show that methylation at 21 of the 32 CpGs predict the development of kidney failure, extending the knowledge and potentially identifying individuals at greater risk for diabetic kidney disease in type 1 diabetes.
The use of virtual fracture clinics across the United Kingdom and Ireland is growing and have been shown in an increasing number of studies to be safe, cost-effective and associated with good ...functional outcomes and patient satisfaction rates for certain fracture types. Initially pioneered at Glasgow Royal Infirmary, many centres have adopted similar templates, or variations of, and the overall aim of this study was to assess functional outcomes and injury recovery satisfaction rates of patients discharged directly following review in a specific virtual fracture clinic model known as the Trauma Assessment Clinic (TAC).
A prospective observational study was carried out of paediatric (aged <17 years) and adult (aged >17 years) patients, with the five most commonly observed fracture types, who were discharged directly following review at the TAC in a single hospital centre over a 12 month period from January to December 2018. Primary and secondary outcomes were assessed via telephone administered questionnaires and patient reported outcome measures (PROMs).
A total of 198 patients were included in the study (n = 98 paediatric and n = 100 adult). Overall, 192 (97%) patients or parents/guardians of patients stated that they either strongly agreed (n = 148, 74.9%) or agreed (n = 44, 22.1%) that they were satisfied with their own or their child's recovery from their injury at a median follow-up of 9 months post direct discharge from the TAC. Adult patients had an EQ-5D-5L index median value of 1 (range 0-1), an EQ-VAS median of 87 (range 0-100), a QuickDASH median score of 0 (range 0-100) and a median LEFS of 80 (range 0-80).
The virtual management of trauma patients via the TAC model is a safe and patient-centred approach to treating certain injuries and fracture patterns. This study reports excellent patient reported outcome measures and patient injury recovery satisfaction rates. The use of current available technology in tandem with up-to-date best clinical practice and guidelines play a central role in this novel care pathway.
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