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BACKGROUND: Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure. METHODS: People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window). FINDINGS: Between Jan 18, 2010, and July 25, 2022, 27â285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32-0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases. INTERPRETATION: Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3-5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand. FUNDING: RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity.
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Falência Renal Crônica , Insuficiência Renal Crônica , Insuficiência Renal , Humanos , Taxa de Filtração Glomerular , Rim , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/terapia , Falência Renal Crônica/etiologia , Radar , Doenças Raras , Sistema de Registros , Insuficiência Renal/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/complicações , Reino Unido/epidemiologia , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou maisRESUMO
This article focuses on bacterial infections that commonly affect geriatric patients. The elderly population is at a higher risk of contracting bacterial infections due to weakened immune systems and comorbidities. The article explores the cause, pathogenesis, clinical manifestations, and treatment options of these infections. Additionally, antibiotic resistance is a growing concern in the treatment of bacterial infections. The article highlights the importance of preventing these infections through proper hygiene and wound care. This article aims to provide an understanding of bacterial infections in geriatric patients and inform health-care providers on the most effective ways to manage and prevent these infections.
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Infecções Bacterianas , Dermatopatias Bacterianas , Infecções dos Tecidos Moles , Humanos , Idoso , Infecções dos Tecidos Moles/diagnóstico , Infecções dos Tecidos Moles/epidemiologia , Infecções dos Tecidos Moles/terapia , Dermatopatias Bacterianas/tratamento farmacológico , Dermatopatias Bacterianas/epidemiologia , Dermatopatias Bacterianas/microbiologia , Pele , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/etiologia , Antibacterianos/uso terapêuticoRESUMO
Wilms tumour (nephroblastoma) is a renal embryonal tumour that is frequently caused by constitutional variants in a small range of cancer predisposition genes. TRIM28 has recently been identified as one such gene. Previously, observational data strongly suggested a parent of origin effect, whereby Wilms tumour only occurred following maternal inheritance of a pathogenic genetic variant. However, here we report a child with bilateral Wilms tumour who had inherited a pathogenic TRIM28 variant from their father. This finding suggests that genetic counselling for paternally inherited pathogenic variants in TRIM28 should include discussion of a potential risk of Wilms tumour.
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Neoplasias Renais , Tumor de Wilms , Criança , Humanos , Masculino , Pai , Rim/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Proteína 28 com Motivo Tripartido/genética , Tumor de Wilms/genética , Tumor de Wilms/patologiaRESUMO
BACKGROUND AND OBJECTIVE: PD-1 inhibitors have revolutionized cancer therapies and are being used to treat an expanding array of cancers. To best serve patients, clinicians should be familiar with the spectrum of skin manifestations associated with PD-1 inhibitor therapy. Here, we report a unique case of hypertrophic lichen planus (HLP) in a 64-year-old man treated with pembrolizumab; the presentation initially suggested a squamous cell carcinoma (SCC) morphology, then evolved into a morphology more typical of hypertrophic lichen planus. This case underscores the need for caution in diagnosing eruptive SCCs associated with PD-1 inhibitor therapy. In such instances, maintaining a high suspicion for lichenoid reactions as sequelae of PD-1 inhibitor treatment and starting an empiric trial of therapy for lichenoid dermatitis may be warranted to ensure timely management of lesions. METHODS: We describe a case of hypertrophic lichen planus mimicking squamous cell carcinoma in the setting of PD-1 inhibitory therapy with pembrolizumab. A PubMed literature review was conducted to identify other cases and determine the incidence of lichenoid reactions imitating squamous cell carcinoma in the setting of PD-1 inhibitor use. RESULTS: Our case is one of the few available pieces of literature describing eruptive hypertrophic lichen planus imitating SCC in the setting of PD-1 inhibitor use. Initial skin nodule biopsy appeared histologically compatible with squamous cell carcinoma. Repeat biopsy of the skin lesions revealed histological features consistent with hypertrophic lichen planus. Over time, lower extremity lesions evolved into a more typical appearance of hypertrophic lichen planus. Treatment with topical 0.05% clobetasol ointment and oral acitretin 25 mg led to complete resolution of lesions within 2-3 months. CONCLUSIONS: This case underscores the significance of maintaining vigilance for lichenoid reactions as potential sequelae of PD-1 inhibitor therapy. It highlights the variability in initial presentation and the potential for lesions to transform over time. Timely recognition and appropriate management, including high-potency topical corticosteroids and oral acitretin, are crucial for achieving favorable outcomes in patients experiencing such reactions. More studies are necessary to fully analyze the rate of HLP occurrence as a consequence of PD-1 inhibitor use.
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Anticorpos Monoclonais Humanizados , Carcinoma de Células Escamosas , Líquen Plano , Humanos , Masculino , Pessoa de Meia-Idade , Líquen Plano/induzido quimicamente , Líquen Plano/patologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/induzido quimicamente , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidoresRESUMO
Children with Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC) experience debilitating pruritus, for which there have been few effective treatment options. In the past 2 years, the ileal bile acid transporter (IBAT) inhibitors maralixibat and odevixibat have been approved for the management of cholestatic pruritus in these individuals, representing an important step forward in improving their quality of life. Emerging data suggest these drugs might also improve event-free survival, therefore potentially altering the typical disease course currently seen in these disorders. This Review will discuss how genetic advances have clarified the molecular basis of cholestatic disorders, facilitating the development of new therapeutic options that have only been evaluated in children. We focus specifically on the newly licensed IBAT inhibitors for patients with Alagille syndrome and PFIC and explore the next steps for these drugs in relation to other paediatric and adult cholestatic disorders, recognising that they have the potential to benefit a wider group of patients with gastrointestinal and liver disease.
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Síndrome de Alagille , Colestase , Criança , Humanos , Síndrome de Alagille/tratamento farmacológico , Qualidade de Vida , Colestase/tratamento farmacológico , Prurido/tratamento farmacológicoRESUMO
In a subset of patients with renal tumours, multiple primary lesions may occur. Predisposition to multiple primary renal tumours (MPRT) is a well-recognised feature of some inherited renal cancer syndromes. The diagnosis of MPRT should therefore provoke a thorough assessment for clinical and genetic evidence of disorders associated with predisposition to renal tumourigenesis. To better define the clinical and genetic characteristics of MPRT, a systematic literature review was performed for publications up to 3 April 2024. A total of 7689 patients from 467 articles were identified with MPRT. Compared to all patients with renal cell carcinoma (RCC), patients with MPRT were more likely to be male (71.8% versus 63%) and have an earlier age at diagnosis (<46 years, 32.4% versus 19%). In 61.1% of cases MPRT were synchronous. The proportion of cases with similar histology and the proportion of cases with multiple papillary renal cell carcinoma (RCC) (16.1%) were higher than expected. In total, 14.9% of patients with MPRT had a family history of cancer or were diagnosed with a hereditary RCC associated syndrome with von Hippel-Lindau (VHL) disease being the most common one (69.7%), followed by Birt-Hogg-Dubé (BHD) syndrome (14.2%). Individuals with a known or likely genetic cause were, on average, younger (43.9 years versus 57.1 years). In rare cases intrarenal metastatic RCC can phenocopy MPRT. We review potential genetic causes of MPRT and their implications for management, suggest an approach to genetic testing for individuals presenting with MPRT and considerations in cases in which routine germline genetic testing does not provide a diagnosis.
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Neoplasias Renais , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/diagnóstico , Doença de von Hippel-Lindau/genética , Doença de von Hippel-Lindau/patologia , Doença de von Hippel-Lindau/complicaçõesRESUMO
Birt-Hogg-Dubé syndrome (BHD syndrome) is an autosomal dominant multisystem disorder with variable expression due to pathogenic constitutional variants in the FLCN gene. Patients with BHD syndrome are predisposed to benign cutaneous fibrofolliculomas/trichodischomas, pulmonary cysts with an associated risk of spontaneous pneumothorax, and renal cell carcinoma. A requirement for updated International consensus recommendations for the diagnosis and management of BHD syndrome was identified. Based on a comprehensive literature review and expert consensus within the fields of respiratory medicine, urology, radiology, dermatology, clinical oncology and clinical genetics, updated recommendations for diagnosis, surveillance and management in BHD syndrome were developed. With the widespread availability of FLCN genetic testing, clinical scenarios in which a diagnosis should be considered and criteria for genetic testing were defined. Following a clinical and/or molecular diagnosis of BHD syndrome, a multidisciplinary approach to disease management is required. Regular renal cancer surveillance is recommended in adulthood and life-long, but the evidence base for additional tumour surveillance is limited and further research warranted. Recommendations for the treatment of cutaneous, pulmonary and renal manifestations are provided. Awareness of BHD syndrome needs to be raised and better knowledge of the clinical settings in which the diagnosis should be considered should enable earlier diagnosis. Further details, including areas for future research topics are available at: https://www.genturis.eu/l=eng/Guidelines-and-pathways/Clinical-practice-guidelines.html .
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BACKGROUND: Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person. Some cases of MLID are caused by trans-acting genetic variants, frequently not in the patients but their mothers, which have counselling implications. There is currently no consensus on the definition of MLID, clinical indications prompting testing, molecular procedures and methods for epigenetic and genetic diagnosis, recommendations for laboratory reporting, considerations for counselling, and implications for prognosis and management. The purpose of this study is thus to cover this unmet need. METHODS: A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations. RESULTS: In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID. CONCLUSIONS: MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3-5 years to evaluate the research advancements and update this guidance as needed.
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Metilação de DNA , Impressão Genômica , Humanos , Impressão Genômica/genética , Metilação de DNA/genética , Testes Genéticos/métodosRESUMO
Introduction: The National Registry of Rare Kidney Diseases (RaDaR) collects data from people living with rare kidney diseases across the UK, and is the world's largest, rare kidney disease registry. We present the clinical demographics and renal function of 25,880 prevalent patients and sought evidence of bias in recruitment to RaDaR. Methods: RaDaR is linked with the UK Renal Registry (UKRR, with which all UK patients receiving kidney replacement therapy [KRT] are registered). We assessed ethnicity and socioeconomic status in the following: (i) prevalent RaDaR patients receiving KRT compared with patients with eligible rare disease diagnoses receiving KRT in the UKRR, (ii) patients recruited to RaDaR compared with all eligible unrecruited patients at 2 renal centers, and (iii) the age-stratified ethnicity distribution of RaDaR patients with autosomal dominant polycystic kidney disease (ADPKD) was compared to that of the English census. Results: We found evidence of disparities in ethnicity and social deprivation in recruitment to RaDaR; however, these were not consistent across comparisons. Compared with either adults recruited to RaDaR or the English population, children recruited to RaDaR were more likely to be of Asian ethnicity (17.3% vs. 7.5%, P-value < 0.0001) and live in more socially deprived areas (30.3% vs. 17.3% in the most deprived Index of Multiple Deprivation (IMD) quintile, P-value < 0.0001). Conclusion: We observed no evidence of systematic biases in recruitment of patients into RaDaR; however, the data provide empirical evidence of negative economic and social consequences (across all ethnicities) experienced by families with children affected by rare kidney diseases.
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Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours that arise not only in adulthood but also in childhood and adolescence. Up to 70-80% of childhood PPGL are hereditary, accounting for a higher incidence of metastatic and/or multifocal PPGL in paediatric patients than in adult patients. Key differences in the tumour biology and management, together with rare disease incidence and therapeutic challenges in paediatric compared with adult patients, mandate close expert cross-disciplinary teamwork. Teams should ideally include adult and paediatric endocrinologists, oncologists, cardiologists, surgeons, geneticists, pathologists, radiologists, clinical psychologists and nuclear medicine physicians. Provision of an international Consensus Statement should improve care and outcomes for children and adolescents with these tumours.
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Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Adulto , Humanos , Criança , Feocromocitoma/genética , Feocromocitoma/terapia , Feocromocitoma/diagnóstico , Paraganglioma/genética , Paraganglioma/terapia , Mutação em Linhagem Germinativa/genética , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/terapia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Succinato Desidrogenase/genéticaRESUMO
We report on an adult woman with rare coexistence of acromegaly, pheochromocytoma (PHEO), gastrointestinal stromal tumor (GIST), intestinal polyposis, and thyroid follicular adenoma. At the age of 56, she was diagnosed with acromegaly caused by a pituitary macroadenoma, treated by transsphenoidal surgery, radiotherapy, and octreotide. During routine colonoscopy, multiple polyps were identified as tubular adenomas with high-grade dysplasia on histology. Years later, an abdominal mass of 8.0 x 6.2 cm was detected by routine ultrasound. Surgical exploration revealed an adrenal mass and another tumor adhered to the lesser gastric curvature, which were removed. Pathology confirmed the diagnosis of PHEO and GIST. PHEO immunohistochemistry was negative for GHRH. During follow-up, nodular goiter was found with normal levels of calcitonin and inconclusive cytology. Near-total thyroidectomy was performed, revealing a follicular adenoma. Her family history was negative for all of these tumor types. Genetic analysis for PHEO/paraganglioma genes (SDH A-D, SDHAF2, RET, VHL, TMEM127, and MAX), and pituitary-related genes (AIP, MEN1, and p27) were negative. Though the finding of PHEO and acromegaly with multiple other tumors could be a fortuitous coexistence, we suggest that this case may represent a new variant of MEN syndrome with a de novo germline mutation in a not yet identified gene. Arq Bras Endocrinol Metab. 2012;56(8):507-12.
Relatamos o caso de uma mulher com rara coexistência de acromegalia, feocromocitoma (FEO), tumor do estroma gastrointestinal (GIST), polipose intestinal e adenoma folicular de tireoide. Aos 56 anos, ela foi diagnosticada com acromegalia por um macroadenoma hipofisário, tratado com cirurgia transesfenoidal, radioterapia e octreotide. Uma colonoscopia de rotina detectou múltiplos pólipos, que à histologia eram adenomas tubulares com alto grau de displasia. Anos mais tarde, uma ecografia detectou uma massa abdominal de 8.0 x 6.2 cm, que na exploração cirúrgica era uma lesão adrenal e outro tumor aderido à pequena curvatura gástrica. A patologia confirmou os diagnósticos de FEO e GIST. A imuno-histoquímica do FEO foi negativa para GHRH. No seguimento, encontrou-se um bócio nodular com níveis normais de calcitonina e citologia inconclusiva. Após tireoidectomia total o diagnóstico histológico foi de adenoma folicular. A história familiar era negativa para todos esses tumores. As análises genéticas para genes de síndromes de FEO/paragangliomas (SDH A-D, SDHAF2, RET, VHL, TMEM127 e MAX) e para hipofisárias (AIP, MEN1 e p27) foram todas negativas. Embora a presença de FEO e acromegalia com múltiplos outros tumores possa ser uma coexistência fortuita, acreditamos na possibilidade de uma nova variante de NEM com uma mutação germinativa de novo em um gene ainda não identificado Arq Bras Endocrinol Metab. 2012;56(8):507-12.