RESUMO
Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the development of hamartomas in the central nervous system, heart, skin, lungs, and kidneys and other manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability. The disease is associated with pathogenic variants in the TSC1 or TSC2 genes, resulting in the hyperactivation of the mTOR pathway, a key regulator of cell growth and metabolism. Consequently, the hyperactivation of the mTOR pathway leads to abnormal tissue proliferation and the development of solid tumors. Kidney involvement in TSC is characterized by the development of cystic lesions, renal cell carcinoma and renal angiomyolipomas, which may progress and cause pain, bleeding, and loss of kidney function. Over the past years, there has been a notable shift in the therapeutic approach to TSC, particularly in addressing renal manifestations. mTOR inhibitors have emerged as the primary therapeutic option, whereas surgical interventions like nephrectomy and embolization being reserved primarily for complications unresponsive to clinical treatment, such as severe renal hemorrhage. This review focuses on the main clinical characteristics of TSC, the mechanisms underlying kidney involvement, the recent advances in therapy for kidney lesions, and the future perspectives.
Resumo O complexo da esclerose tuberosa (CET) é uma doença autossômica dominante caracterizada pelo desenvolvimento de hamartomas no sistema nervoso central, coração, pele, pulmões e rins e outras manifestações, incluindo convulsões, tubérculos corticais, linhas de migração radial, autismo e deficiência cognitiva. A doença está associada a variantes patogênicas nos genes TSC1 ou TSC2, resultando na hiperativação da via mTOR, um importante regulador do crescimento e metabolismo celular. Consequentemente, a hiperativação da via mTOR leva à proliferação anormal do tecido e ao desenvolvimento de tumores sólidos. O envolvimento renal no CET é caracterizado pelo desenvolvimento de lesões císticas, carcinoma de células renais e angiomiolipomas renais, que podem progredir e causar dor, sangramento e perda da função renal. Nos últimos anos, houve uma mudança notável na abordagem terapêutica do CET, especialmente no tratamento das manifestações renais. Os inibidores de mTOR surgiram como a principal opção terapêutica, enquanto intervenções cirúrgicas como nefrectomia e embolização são reservadas principalmente para complicações que não respondem ao tratamento clínico, como hemorragia renal grave. Esta revisão se concentra nas principais características clínicas do CET, nos mecanismos subjacentes ao envolvimento renal, nos recentes avanços na terapia para lesões renais e nas perspectivas futuras.
RESUMO
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the development of hamartomas in the central nervous system, heart, skin, lungs, and kidneys and other manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability. The disease is associated with pathogenic variants in the TSC1 or TSC2 genes, resulting in the hyperactivation of the mTOR pathway, a key regulator of cell growth and metabolism. Consequently, the hyperactivation of the mTOR pathway leads to abnormal tissue proliferation and the development of solid tumors. Kidney involvement in TSC is characterized by the development of cystic lesions, renal cell carcinoma and renal angiomyolipomas, which may progress and cause pain, bleeding, and loss of kidney function. Over the past years, there has been a notable shift in the therapeutic approach to TSC, particularly in addressing renal manifestations. mTOR inhibitors have emerged as the primary therapeutic option, whereas surgical interventions like nephrectomy and embolization being reserved primarily for complications unresponsive to clinical treatment, such as severe renal hemorrhage. This review focuses on the main clinical characteristics of TSC, the mechanisms underlying kidney involvement, the recent advances in therapy for kidney lesions, and the future perspectives.
Assuntos
Esclerose Tuberosa , Esclerose Tuberosa/complicações , Esclerose Tuberosa/genética , Esclerose Tuberosa/terapia , Humanos , Neoplasias Renais/terapia , Neoplasias Renais/etiologia , Inibidores de MTOR/uso terapêutico , Serina-Treonina Quinases TOR , Angiomiolipoma/etiologia , Angiomiolipoma/terapia , Nefrologia , Proteína 1 do Complexo Esclerose Tuberosa/genética , Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/genéticaRESUMO
Podocyte dysfunction plays a crucial role in renal injury and is identified as a key contributor to proteinuria in Fabry disease (FD), primarily impacting glomerular filtration function (GFF). The α3ß1 integrins are important for podocyte adhesion to the glomerular basement membrane, and disturbances in these integrins can lead to podocyte injury. Therefore, this study aimed to assess the effects of chloroquine (CQ) on podocytes, as this drug can be used to obtain an in vitro condition analogous to the FD. Murine podocytes were employed in our experiments. The results revealed a dose-dependent reduction in cell viability. CQ at a sub-lethal concentration (1.0 µg/mL) induced lysosomal accumulation significantly (p < 0.0001). Morphological changes were evident through scanning electron microscopy and immunofluorescence, highlighting alterations in F-actin and nucleus morphology. No significant changes were observed in the gene expression of α3ß1 integrins via RT-qPCR. Protein expression of α3 integrin was evaluated with Western Blotting and immunofluorescence, demonstrating its lower detection in podocytes exposed to CQ. Our findings propose a novel in vitro model for exploring secondary Fabry nephropathy, indicating a modulation of α3ß1 integrin and morphological alterations in podocytes under the influence of CQ.
Assuntos
Doença de Fabry , Integrina alfa3beta1 , Nefropatias , Podócitos , Animais , Camundongos , Doença de Fabry/metabolismo , Integrina alfa3beta1/genética , Integrina alfa3beta1/metabolismo , Nefropatias/metabolismo , Podócitos/metabolismo , Insuficiência RenalRESUMO
Renal osteodystrophy (ROD) starts early and progresses with further loss of kidney function in patients with chronic kidney disease (CKD). There are four distinct types of ROD based on undecalcified bone biopsy results. Adynamic bone disease and osteomalacia are the predominant forms of low bone turnover, while hyperparathyroid bone disease and mixed uremic osteodystrophy (MUO) are typically associated with high bone turnover. MUO is a prevalent but poorly described pathology that demonstrates evidence of osteomalacia on top of the high bone formation/resorption. The prevalence of MUO ranges from 5 to 63% among different studies. The pathogenesis of MUO is multi-factorial. Altered phosphate homeostasis, hypocalcemia, vitamin D deficiency, increased FGF-23, interleukins 1 and 6, TNF-α, amyloid, and heavy metal accumulation are the main inducers of MUO. The clinical findings of MUO are usually non-specific. The use of non-invasive testing such as bone turnover markers and imaging techniques might help to suspect MUO. However, it is usually impossible to precisely diagnose this condition without performing bone biopsy. The principal management of MUO is to control the maladaptive hyperparathyroidism along with correcting any nutritional mineral deficiencies that may induce mineralization defect. MUO is a common but still poorly understood bone pathology category; it demonstrates the complexity and difficulty in understanding ROD. A large prospective bone biopsy-based studies are needed for better identification as proper diagnosis and management would improve the outcome of patients with MUO.
Assuntos
Doenças Ósseas Metabólicas , Reabsorção Óssea , Distúrbio Mineral e Ósseo na Doença Renal Crônica , Osteomalacia , Insuficiência Renal Crônica , Humanos , Osteomalacia/complicações , Estudos Prospectivos , Osso e Ossos , Insuficiência Renal Crônica/complicações , Doenças Ósseas Metabólicas/complicações , Distúrbio Mineral e Ósseo na Doença Renal Crônica/complicaçõesAssuntos
Angiomiolipoma , Neoplasias Renais , Esclerose Tuberosa , Humanos , Esclerose Tuberosa/complicações , Esclerose Tuberosa/tratamento farmacológico , Angiomiolipoma/complicações , Angiomiolipoma/tratamento farmacológico , Inibidores de MTOR , Neoplasias Renais/complicações , Neoplasias Renais/tratamento farmacológico , Serina-Treonina Quinases TORRESUMO
Fanconi anemia (FA) is a rare disease characterized by progressive bone marrow failure, cancer predisposition, and multiple systemic malformations, including congenital abnormalities of the kidney and urinary tract (CAKUT). Hematopoietic cell transplantation (HCT), the only potentially curative treatment for the hematological complications of FA, may precipitate acute kidney injury (AKI) and hypertension. We retrospectively investigated 107 FA patients who underwent HCT between 2009 and 2017. We investigated the incidence and risk factors of AKI within 100 days after HCT in a cohort of FA patients, and kidney function and hypertension over 2-year follow-up.The incidence of AKI (mainly stage I) was 18.7%. Patients aged ≥ 11 years at transplantation showed a higher risk of AKI (OR 3.53). The eGFR was 60-90 mL/min/1.73 m2 in 53 (49.5%), 55 (51.4%), 50 (50.5%), 50 (51%), and 46 (59.7%) patients before HCT, at 100 days, 6 months, 1 year, and 2 years. Within the first 100 days after HCT, hypertension was observed in 72% of the patients and was associated with cyclosporine therapy. Most (62.3%) patients had stage 2 hypertension. CAKUT was observed in 33.7% of the patients and was associated with both hypertension (86%) and diminished kidney function but not with AKI.Conlusion: Although AKI, a commonly known HCT complication, was mild in this study, the prevalence of chronic kidney disease (CKD), as well as the high incidence of hypertension, specially associated with CAKUT point out the importance of kidney care in short and long-term follow up of FA patients. What is Known: ⢠Fanconi anemia (FA) is the most frequent inherited bone marrow failure in children, and 30% of cases have congenital anomalies of kidney (CAKUT). ⢠Acute kidney injury and hypertension after hematopoietic cell transplantation (HCT) may impact the outcomes.. What is New: ⢠Despite the presence of CAKUT and stage 2 CKD in 33.7% and 50% of the patients, respectively, AKI was mild and transitory after HCT in FA patients. ⢠CAKUT in FA patients was associated with lower kidney function and hypertension after HCT.
Assuntos
Injúria Renal Aguda , Anemia de Fanconi , Transplante de Células-Tronco Hematopoéticas , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Criança , Anemia de Fanconi/complicações , Anemia de Fanconi/epidemiologia , Anemia de Fanconi/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Rim , Estudos RetrospectivosRESUMO
OBJECTIVES: To evaluate the health-condition of military police officers and firefighters. To identify risk factors for not being medically ready for duty. DESIGN: Cross-sectional study. SETTING: Data were extracted from medical records during annual periodic health assessments of police officers and firefighters serving with the military police in Paraná, Brazil. PARTICIPANTS: 6621 police officers (5927 men and 694 women) and 1347 firefighters (1257 men and 90 women) who underwent health assessments between July 2018 and June 2019 were analysed. Pregnant women were excluded. OUTCOME MEASURES: Data included variables such as sex, age, anthropometric measurements, lifestyle, comorbidities and laboratory tests. Multiple logistic regression was used to estimate the probability of not being medically ready for active duty. RESULTS: Overall, police officers had worse health status than firefighters and greater prevalence of overweight and obesity, regardless of sex. Musculoskeletal diseases were the most commonly reported disease by police officers and firefighters of both sexes. Among men, hypertension was the second most prevalent disease, followed by psychiatric diseases and dyslipidaemia. Among women, psychiatric diseases were the second most prevalent. Male police officers ≥40 years old presented the highest probability of not being considered ready for duty (40.1%). The probability of male police officers between the ages of 31 and 40 not being ready was similar to that for male firefighters >40 years old. There was a higher chance of not being medically ready professionals with diseases such as diabetes mellitus (OR 2.95, 95% CI 1.97 to 5.03), dyslipidaemia (OR 2.65, 95% CI 1.96 to 3.58), hypertension (OR 2.29, 95% CI 1.85 to 4.70), high total cholesterol (OR 2.16, 95% CI 1.93 to 2.42), and heart disease (OR 2.13, 95% CI 1.32 to 3.45). CONCLUSIONS: There was a high prevalence of chronic diseases and modifiable cardiovascular risk factors among police officers and firefighters. Healthy protective measures should be offered frequently, particularly to police officers at an earlier age.
Assuntos
Bombeiros , Hipertensão , Gravidez , Humanos , Masculino , Feminino , Adulto , Polícia/psicologia , Estudos Transversais , Bombeiros/psicologia , Brasil , Nível de SaúdeAssuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica , Insuficiência Renal Crônica , Brasil , Distúrbio Mineral e Ósseo na Doença Renal Crônica/diagnóstico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/terapia , Humanos , Minerais , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/terapiaRESUMO
PURPOSE OF REVIEW: In this narrative review, we describe general aspects, histological alterations, treatment, and implications of Fabry disease (FD) nephropathy. This information should be used to guide physicians and patients in a shared decision-making process. SOURCE OF INFORMATION: Original peer-reviewed articles, review articles, and opinion pieces were identified from PubMed and Google Scholar databases. Only sources in English were accessed. METHODS: We performed a focused narrative review assessing the main aspects of FD nephropathy. The literature was critically analyzed from a theoretical and contextual perspective, and thematic analysis was performed. KEY FINDINGS: FD nephropathy is related to the progressive accumulation of GL3, which occurs in all types of renal cells. It is more prominent in podocytes, which seem to play an important role in the pathogenesis of this nephropathy. A precise detection of renal disorders is of fundamental importance because the specific treatment of FD is usually delayed, making reversibility unlikely and leading to a worse prognosis. LIMITATIONS: As no formal tool was applied to assess the quality of the included studies, selection bias may have occurred. Nonetheless, we have attempted to provide a comprehensive review on the topic using current studies from experts in FD and extensive review of the literature.
OBJET DE LA REVUE: Dans cette revue narrative, nous discutons des aspects généraux, des modifications histologiques, du traitement et des implications de la néphropathie liée à la Maladie de Fabry. Des informations qui serviront à guider les médecins et les patients dans un processus commun de prise de décision. SOURCES: Les originaux d'articles évalués par les pairs, d'articles-synthèses et d'articles d'opinion ont été répertoriés dans les bases de données Pubmed et Google Scholar. Seuls les articles en anglais ont été consultés. MÉTHODOLOGIE: Nous avons procédé à une revue narrative ciblée examinant les principaux aspects de la néphropathie liés à la maladie de Fabry. La documentation a fait l'objet d'une critique rigoureuse du point de vue théorique et contextuel, et une analyse thématique a été effectuée. PRINCIPAUX RÉSULTATS: La néphropathie liée à la maladie de Fabry est associée à l'accumulation progressive de GL3, qui se produit dans tous les types de cellules rénales. Elle est plus présente dans les podocytes, qui semblent jouer un rôle important dans la pathogenèse de la néphropathie. Un dépistage précis des troubles rénaux est d'une importance capitale puisque le traitement spécifique de la maladie de Fabry est généralement retardé, ce qui rend la réversibilité peu probable et conduit à un pronostic plus défavorable. LIMITES: Des biais de sélection pourraient s'être introduits puisqu'aucun outil formel n'a été utilisé pour évaluer les études incluses. Nous avons néanmoins tenté de procéder à un examen complet du sujet grâce aux études actuelles menées par des experts de la maladie de Fabry et à une revue approfondie de la documentation.