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1.
Transplant Proc ; 51(2): 545-547, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30879586

RESUMO

BACKGROUND: Cystinosis is a rare genetic disorder characterized by the abnormal accumulation of cystine in the lysosomes of various tissues and organs leading to their dysfunction. The most common type is the infantile nephropathic cystinosis which without treatment leads to renal failure and before the introduction of cysteamine was the cause of death before puberty. CASE PRESENTATION: A 27-year-old female patient with infantile cystinosis developed end-stage renal disease at the age of 10. The first kidney transplantation from patient's father was carried out at the age of 12. The recurrent urinary tract infections led to the graft failure after 6 years. Following the removal of right appendages due to the ovarian tumor, the patient underwent the second kidney transplantation from her mother at the age of 19. After the transplantation, the cysteamine treatment was irregular due to limited availability of the medicine. When it became regular in 2017 the patient did not tolerate full doses. Despite elevated blood levels of cystine and the removal of right appendages, the patient naturally became pregnant in August 2017. Except for recurrent urinary tract infections, the renal parameters remained normal throughout the entire pregnancy. However, in the 32nd week of gestation, due to preeclampsia a caesarean section was performed. A healthy daughter was born, 1400/41 and with a 9 point Apgar score. CONCLUSIONS: Due to the possibility of treatment with cysteamine and kidney transplantations, patients with cystinosis live longer and their quality of life improves. These female patients can even naturally become pregnant and give birth to healthy children.


Assuntos
Cistinose , Complicações na Gravidez , Adulto , Cesárea , Cisteamina/uso terapêutico , Eliminadores de Cistina/uso terapêutico , Cistinose/terapia , Feminino , Humanos , Transplante de Rim , Gravidez , Resultado da Gravidez
2.
J. bras. nefrol ; 41(1): 131-141, Jan.-Mar. 2019. tab
Artigo em Inglês | LILACS | ID: biblio-1002426

RESUMO

Abstract Care for patients with chronic and rare diseases is complex, especially considering the lack of knowledge about the disease, which makes early and precise diagnosis difficult, as well as the need for specific tests, sometimes of high complexity and cost. Added to these factors are difficulties in obtaining adequate treatment when available, in raising patient and family awareness about the disease and treatment compliance. Nephropathic cystinosis is among these diseases. After more than 20 years as a care center for these patients, the authors propose a follow-up protocol, which has been used with improvement in the quality of care and consists of a multidisciplinary approach, including care provided by a physician, nurse, psychologist, nutritionist and social worker. In this paper, each field objectively exposes how to address points that involve the stages of diagnosis and its communication with the patient and their relatives or guardians, covering the particularities of the disease and the treatment, the impact on the lives of patients and families, the approach to psychological and social issues and guidelines on medications and diets. This protocol could be adapted to the follow-up of patients with other rare diseases, including those with renal involvement. This proposal is expected to reach the largest number of professionals involved in the follow-up of these patients, strengthening the bases for the creation of a national protocol, observing the particularities of each case.


Resumo A assistência a pacientes com doenças crônicas e raras é complexa, principalmente pela falta de disseminação de conhecimento sobre a doença, o que dificulta o diagnóstico preciso e precoce, além da necessidade da realização de exames específicos, por vezes de alta complexidade e custo. Somam-se a esses fatores dificuldades na obtenção de tratamento adequado quando disponível, na conscientização do paciente e da família sobre a doença e na aderência ao tratamento. A cistinose nefropática está entre essas doenças. Após mais de 20 anos como centro de atendimento a esses pacientes, os autores propõem um protocolo de seguimento, o qual vem sendo empregado com melhora na qualidade da assistência e consiste de uma abordagem multidisciplinar, incluindo, principalmente, atendimento prestado por médico, enfermeiro, psicólogo, nutricionista e assistente social. Neste artigo, cada área expõe de maneira objetiva como abordar pontos que envolvem as etapas do diagnóstico e sua comunicação ao paciente e a seus familiares ou responsáveis, abrangendo as particularidades da doença e do tratamento, o impacto na vida do paciente e de sua família, a abordagem das questões psicológicas e sociais e orientações quanto a medicamentos e dietas. Considera-se que este protocolo poderia ser adaptado ao seguimento de pacientes portadores de outras doenças raras, incluindo aquelas com envolvimento renal. Com essa proposta, espera-se alcançar o maior número de profissionais envolvidos no seguimento desses pacientes, fortalecendo as bases para a criação de um protocolo nacional, observando-se as particularidades de cada caso.


Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Adulto , Adulto Jovem , Cistinose/diagnóstico , Cistinose/terapia , Doenças Raras/diagnóstico , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/tratamento farmacológico , Equipe de Assistência ao Paciente , Gravidez , Protocolos Clínicos , Diálise Renal , Transplante de Rim , Resultado do Tratamento , Cistinose/complicações , Cistinose/psicologia , Doenças Raras/complicações , Doenças Raras/psicologia , Doenças Raras/tratamento farmacológico , Diálise , Síndrome de Fanconi/complicações , Síndrome de Fanconi/psicologia , Falência Renal Crônica/etiologia
3.
Pediatr Nephrol ; 34(6): 965-973, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29789935

RESUMO

Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders (LSDs). Initial symptoms of cystinosis correspond to the renal Fanconi syndrome. Patients then develop chronic kidney disease and multi-organ failure due to accumulation of cystine in all tissue compartments. LSDs are commonly characterized by a defective activity of lysosomal enzymes. Hematopoietic stem and progenitor cell (HSPC) transplantation is a treatment option for several LSDs based on the premise that their progeny will integrate in the affected tissues and secrete the functional enzyme, which will be recaptured by the surrounding deficient cells and restore physiological activity. However, in the case of cystinosis, the defective protein is a transmembrane lysosomal protein, cystinosin. Thus, cystinosin cannot be secreted, and yet, we showed that HSPC transplantation can rescue disease phenotype in the mouse model of cystinosis. In this review, we are describing a different mechanism by which HSPC-derived cells provide cystinosin to diseased cells within tissues, and how HSPC transplantation could be an effective one-time treatment to treat cystinosis but also other LSDs associated with a lysosomal transmembrane protein dysfunction.


Assuntos
Cistinose/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Animais , Humanos
4.
Am J Transplant ; 18(11): 2823-2828, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30030899

RESUMO

Cystinosis is an autosomal recessive lysosomal storage disorder characterized by the defective transport of the amino acid cystine out of the lysosome due to a deficiency of cystinosin, the lysosomal cystine transporter. Patients have lysosomal cystine accumulation in various tissues, leading to cellular stress and damage, particularly in the kidney, cornea, and other extrarenal tissues. Cysteamine, a cystine-depleting agent, improves survival and delays the progression of disease, but it does not prevent the development of either renal failure or extrarenal complications. Furthermore, the drug has severe adverse effects that significantly reduce patient compliance. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently established as a therapeutic option for many inborn errors of metabolism, where the main pathologic driving factor is an enzyme deficiency. Recent studies in the cystinosis mouse-model suggested that HSCT could be a curative treatment alternative to cysteamine therapy. We treated a 16-year-old boy who had infantile cystinosis and side effects of cysteamine therapy with HSCT. We were able to demonstrate successful transfer of the wild-type cystinosin protein and CTNS mRNA to nonhematological epithelial cells in the recipient, as well as a decrease in the tissue cystine-crystal burden. This is the first report of allogeneic HSCT in a patient with cystinosis, the prototype of lysosomal membrane-transporter disorders.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/administração & dosagem , Cistinose/terapia , Células Epiteliais/metabolismo , Transplante de Células-Tronco Hematopoéticas , Adolescente , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Cistinose/genética , Humanos , Masculino , Mutação , Prognóstico , Transplante Homólogo
5.
Iran J Kidney Dis ; 12(1): 61-63, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29421779

RESUMO

Cystinosis is a rare autosomal recessive disorder resulting from defective lysosomal transport of cystine due to mutations in the cystinosin lysosomal cystine transporter (CTNS) gene. The clinical phenotype of nephropathic cystinosis is characterized by renal tubular Fanconi syndrome and development of end-stage renal disease during the first decade. Although metabolic acidosis is the classically prominent finding of the disease, a few cases may present with hypokalemic metabolic alkalosis mimicking Bartter syndrome. Bartter-like presentation may lead to delay in diagnosis and initiation of specific treatment for cystinosis. We report a case of a 6-year-old girl initially presenting with the features of Bartter syndrome that was diagnosed 2 years later with nephropathic cystinosis and a novel CTNS mutation.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/genética , Síndrome de Bartter/diagnóstico , Cistinose/diagnóstico , Cistinose/genética , Mutação , Alcalose/etiologia , Criança , Cistinose/complicações , Cistinose/terapia , Análise Mutacional de DNA , Diagnóstico Diferencial , Progressão da Doença , Feminino , Predisposição Genética para Doença , Humanos , Hipopotassemia/etiologia , Falência Renal Crônica/etiologia , Diálise Peritoneal , Fenótipo , Valor Preditivo dos Testes
6.
Saudi J Kidney Dis Transpl ; 28(5): 1180-1183, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28937083

RESUMO

Cystinosis is an autosomal recessive, lysosomal storage disease characterised by the accumulation of the amino acid cystine in different organs and tissues. It is a multisystemic disease that can present with renal and extra-renal manifestations. In this report, we present the first case of transplanted nephropathic cystinosis in a Tunisian child. A 4-year-old Tunisian boy born to nonconsanguineous parents, was treated in our medical services in 1990 for cystinosis. Since the age of five months, he developed symptoms of severe weight loss, vomiting, dehydration, and polyuria. He manifested the Toni Debré Fanconi syndrome. Slit lamp examination of the anterior segment of both eyes revealed fine, shiny crystal-like deposits diffusely distributed in the corneal epithelium and the stroma. Our patient had renal failure. At the age of seven, he reached terminal chronic renal failure and was treated with peritoneal dialysis. Hemodialysis was started at the age of nine years. At the age of 13 years, he received a renal transplantation and was started on cysteamine 1999, five months after the renal transplantation. Currently, the patient is 28-year-old. The graft has survived 15 years after the transplantation. Renal functions were stable with a serum creatinine of 123 µmol/L at last follow-up.


Assuntos
Cistinose/terapia , Síndrome de Fanconi/terapia , Falência Renal Crônica/terapia , Transplante de Rim , Diálise Renal , Pré-Escolar , Cisteamina/uso terapêutico , Cistinose/complicações , Cistinose/diagnóstico , Progressão da Doença , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/etiologia , Sobrevivência de Enxerto , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/etiologia , Masculino , Diálise Peritoneal , Fatores de Tempo , Resultado do Tratamento
7.
BMC Nephrol ; 18(1): 210, 2017 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-28673276

RESUMO

BACKGROUND: Nephropathic cystinosis is a rare inherited metabolic disorder leading to progressive renal failure and extra-renal comorbidity. The prognosis relies on early adherence to cysteamine treatment and symptomatic therapies. Developing nations [DiN] experience many challenges for management of cystinosis. The aim of this study was to assess the management characteristics in DiN compared with developed nations [DeN]. METHODS: A questionnaire was sent between April 2010 and May 2011 to 87 members of the International Pediatric Nephrology Association, in 50 countries. RESULTS: A total of 213 patients were included from 41 centres in 30 nations (109 from 17 DiN and 104 from 13 DeN). 7% of DiN patients died at a median age of 5 years whereas no death was observed in DeN. DiN patients were older at the time of diagnosis. In DiN, leukocyte cystine measurement was only available in selected cases for diagnosis but never for continuous monitoring. More patients had reached end-stage renal disease in DiN (53.2 vs. 37.9%, p = 0.03), within a shorter time of evolution (8 vs. 10 yrs., p = 0.0008). The earlier the cysteamine treatment, the better the renal outcome, since the median renal survival increased up to 16.1 [12.5-/] yrs. in patients from DeN treated before the age of 2.5 years of age (p = 0.0001). However, the renal survival was not statistically different between DeN and DiN when patients initiated cysteamine after 2.5 years of age. The number of transplantations and the time from onset of ESRD to transplantation were not different in DeN and DiN. More patients were kept under maintenance dialysis in DiN (26% vs.19%, p = 0.02); 79% of patients from DiN vs. 45% in DeN underwent peritoneal dialysis. CONCLUSIONS: Major discrepancies between DiN and DeN in the management of nephropathic cystinosis remain a current concern for many patients living in countries with limited financial resources.


Assuntos
Cistinose/epidemiologia , Saúde Global , Internacionalidade , Falência Renal Crônica/epidemiologia , Médicos , Inquéritos e Questionários , Adolescente , Adulto , Criança , Pré-Escolar , Cistinose/diagnóstico , Cistinose/terapia , Países em Desenvolvimento , Feminino , Seguimentos , Humanos , Lactente , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/terapia , Masculino , Estudos Retrospectivos , Adulto Jovem
8.
J Inherit Metab Dis ; 40(4): 555-567, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28643139

RESUMO

Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides "proof of principle" that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH, and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since, in general, Arg to Cys changes comprise about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases.


Assuntos
Arginina/química , Cisteamina/química , Cisteína/química , Cistinose/terapia , Mutação , Animais , Apolipoproteína E3/metabolismo , Argininossuccinato Liase/metabolismo , Cistationina beta-Sintase/metabolismo , Cistinose/genética , Cistinose/metabolismo , Homeostase , Humanos , Concentração de Íons de Hidrogênio , Conformação Molecular , Mutação de Sentido Incorreto , Oxirredução , Compostos de Sulfidrila/química , Tromboplastina/metabolismo
9.
Curr Opin Pediatr ; 29(2): 168-178, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28107209

RESUMO

PURPOSE OF REVIEW: Over the past few decades, cystinosis, a rare lysosomal storage disorder, has evolved into a treatable metabolic disease. The increasing understanding of its pathophysiology has made cystinosis a prototype disease, delivering new insights into several fundamental biochemical and cellular processes. RECENT FINDINGS: In this review, we aim to provide an overview of the latest advances in the pathogenetic, clinical, and therapeutic aspects of cystinosis. SUMMARY: The development of alternative therapeutic monitoring strategies and new systemic and ocular cysteamine formulations might improve outcome of cystinosis patients in the near future. With the dawn of stem cell based therapy and new emerging gene-editing technologies, novel tools have become available in the search for a cure for cystinosis.


Assuntos
Cisteamina/uso terapêutico , Cistinose/diagnóstico , Cistinose/terapia , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/terapia , Feminino , Previsões , Terapia Genética/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Medição de Risco , Índice de Gravidade de Doença , Transplante de Células-Tronco/métodos , Resultado do Tratamento
10.
Nat Rev Nephrol ; 13(2): 115-131, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27990015

RESUMO

Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. It is caused by a defect in the lysosomal cystine transporter, cystinosin, which results in an accumulation of cystine in all organs. Despite the ubiquitous expression of cystinosin, a renal Fanconi syndrome is often the first manifestation of cystinosis, usually presenting within the first year of life and characterized by the early and severe dysfunction of proximal tubule cells, highlighting the unique vulnerability of this cell type. The current therapy for cystinosis, cysteamine, facilitates lysosomal cystine clearance and greatly delays progression to kidney failure but is unable to correct the Fanconi syndrome. This Review summarizes decades of studies that have fostered a better understanding of the pathogenesis of the renal Fanconi syndrome associated with cystinosis. These studies have unraveled some of the early molecular changes that occur before the onset of tubular atrophy and identified a role for cystinosin beyond cystine transport, in endolysosomal trafficking and proteolysis, lysosomal clearance, autophagy and the regulation of energy balance. These studies have also led to the identification of new potential therapeutic targets and here, we outline the potential role of stem cell therapy for cystinosis and provide insights into the mechanism of haematopoietic stem cell-mediated kidney protection.


Assuntos
Cistinose/complicações , Cistinose/terapia , Síndrome de Fanconi/etiologia , Síndrome de Fanconi/terapia , Cristalização , Cistina/fisiologia , Cistinose/metabolismo , Previsões , Humanos , Estresse Oxidativo
11.
Nefrología (Madr.) ; 36(6): 616-630, nov.-dic. 2016. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-158751

RESUMO

Introducción: El aumento de la supervivencia de los pacientes con cistinosis y la propia complejidad de la enfermedad explican la necesidad de implementar un proceso de transición guiada desde la medicina pediátrica hasta la del adulto, que permita garantizar el continuumasistencial y posibilite el empoderamiento del paciente desde el cuidado tutelado al autocuidado. Métodos: Revisión bibliográfica, opinión de expertos, encuestas anónimas a pacientes, familiares y asociaciones. Resultados: Elaboración de un documento de transición coordinada, con propuestas concretas por especialidades y de mejora de la adherencia terapéutica y del autocuidado del paciente. El nefrólogo desempeña un papel clave en la transición en la cistinosis debido a la afectación renal que domina la patología y porque la mayoría de los pacientes han recibido un trasplante renal antes de la edad adulta. Conclusión: Se presenta un documento que establece unas recomendaciones y un cronograma para guiar la transición de los adolescentes y adultos jóvenes con cistinosis en nuestro ámbito (AU)


Introduction: Improved outcome and longer life-expectancy in patients with cystinosis, and disease complexity itself, justify planning a guided-transition of affected patients from Pediatrics to adult medicine. The aims of the process are to guarantee the continuum of care and patient empowerment, moving from guardian-care to self-care. Methods: review of articles, expert opinion and anonymous surveys of patients, relatives and patient advocacy groups. Results: elaboration a new document to support and coordinate the transition of patients with cystinosis providing specific proposals in a variety of medical fields, and adherence promotion. Nephrologists play a key role in transition due the fact that most cystinotic patients suffer severe chronic kidney disease, and need kidney transplantation before adulthood. Conclusion: we present a document providing recommendations and suggesting a chronogram to help the process of transition of adolescents and young adults with cystinosis in our area (AU)


Assuntos
Humanos , Adolescente , Adulto Jovem , Cistinose/terapia , Planejamento de Assistência ao Paciente/organização & administração , Cuidado Transicional/organização & administração , Padrões de Prática Médica , Insuficiência Renal Crônica/prevenção & controle , Doenças Raras/epidemiologia , Perfil de Impacto da Doença
12.
Nefrologia ; 36(6): 616-630, 2016.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-27595514

RESUMO

INTRODUCTION: Improved outcome and longer life-expectancy in patients with cystinosis, and disease complexity itself, justify planning a guided-transition of affected patients from Pediatrics to adult medicine. The aims of the process are to guarantee the continuum of care and patient empowerment, moving from guardian-care to self-care. METHODS: review of articles, expert opinion and anonymous surveys of patients, relatives and patient advocacy groups. RESULTS: elaboration a new document to support and coordinate the transition of patients with cystinosis providing specific proposals in a variety of medical fields, and adherence promotion. Nephrologists play a key role in transition due the fact that most cystinotic patients suffer severe chronic kidney disease, and need kidney transplantation before adulthood. CONCLUSION: we present a document providing recommendations and suggesting a chronogram to help the process of transition of adolescents and young adults with cystinosis in our area.


Assuntos
Cistinose/terapia , Transição para Assistência do Adulto , Adolescente , Adulto , Criança , Humanos , Transplante de Rim , Pediatria , Insuficiência Renal Crônica/terapia , Autocuidado , Adulto Jovem
13.
Kidney Int ; 89(6): 1192-203, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27181776

RESUMO

Nephropathic cystinosis is an autosomal recessive metabolic, lifelong disease characterized by lysosomal cystine accumulation throughout the body that commonly presents in infancy with a renal Fanconi syndrome and, if untreated, leads to end-stage kidney disease (ESKD) in the later childhood years. The molecular basis is due to mutations in CTNS, the gene encoding for the lysosomal cystine-proton cotransporter, cystinosin. During adolescence and adulthood, extrarenal manifestations of cystinosis develop and require multidisciplinary care. Despite substantial improvement in prognosis due to cystine-depleting therapy with cysteamine, no cure of the disease is currently available. Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference on cystinosis to review the state-of-the-art knowledge and to address areas of controversies in pathophysiology, diagnostics, monitoring, and treatment in different age groups. More importantly, promising areas of investigation that may lead to optimal outcomes for patients afflicted with this lifelong, systemic disease were discussed with a research agenda proposed for the future.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/genética , Cisteamina/uso terapêutico , Eliminadores de Cistina/uso terapêutico , Cistina/metabolismo , Cistinose/etiologia , Doenças Raras/etiologia , Adolescente , Adulto , Fatores Etários , Criança , Congressos como Assunto , Cisteamina/efeitos adversos , Eliminadores de Cistina/efeitos adversos , Cistinose/complicações , Cistinose/diagnóstico , Cistinose/terapia , Síndrome de Fanconi/complicações , Síndrome de Fanconi/tratamento farmacológico , Testes Genéticos , Terapia Genética , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunossupressão/efeitos adversos , Lactente , Falência Renal Crônica/etiologia , Transplante de Rim/efeitos adversos , Lisossomos/metabolismo , Mutação , Doenças Raras/complicações , Doenças Raras/diagnóstico , Doenças Raras/terapia , Diálise Renal
14.
Endocrinology ; 157(4): 1363-71, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26812160

RESUMO

Hypothyroidism is the most frequent and earliest endocrine complication in cystinosis, a multisystemic lysosomal storage disease caused by defective transmembrane cystine transporter, cystinosin (CTNS gene). We recently demonstrated in Ctns(-/-) mice that altered thyroglobulin biosynthesis associated with endoplasmic reticulum stress, combined with defective lysosomal processing, caused hypothyroidism. In Ctns(-/-) kidney, hematopoietic stem cell (HSC) transplantation provides long-term functional and structural protection. Tissue repair involves transfer of cystinosin-bearing lysosomes from HSCs differentiated as F4/80 macrophages into deficient kidney tubular cells, via tunneling nanotubes that cross basement laminae. Here we evaluated the benefit of HSC transplantation for cystinotic thyroid and investigated the underlying mechanisms. HSC engraftment in Ctns(-/-) thyroid drastically decreased cystine accumulation, normalized the TSH level, and corrected the structure of a large fraction of thyrocytes. In the thyroid microenvironment, HSCs differentiated into a distinct, mixed macrophage/dendritic cell lineage expressing CD45 and major histocompatibility complex II but low CD11b and F4/80. Grafted HSCs closely apposed to follicles and produced tunneling nanotube-like extensions that crossed follicular basement laminae. HSCs themselves further squeezed into follicles, allowing extensive contact with thyrocytes, but did not transdifferentiate into Nkx2.1-expressing cells. Our observations revealed significant differences of basement lamina porosity between the thyroid and kidney and/or intrinsic macrophage invasive properties once in the thyroid microenvironment. The contrast between extensive thyrocyte protection and low HSC abundance at steady state suggests multiple sequential encounters and/or remanent impact. This is the first report demonstrating the potential of HSC transplantation to correct thyroid disease and supports a major multisystemic benefit of stem cell therapy for cystinosis.


Assuntos
Cistinose/terapia , Modelos Animais de Doenças , Transplante de Células-Tronco Hematopoéticas/métodos , Glândula Tireoide/fisiopatologia , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Animais , Diferenciação Celular , Cistina/metabolismo , Cistinose/genética , Cistinose/fisiopatologia , Feminino , Células-Tronco Hematopoéticas/metabolismo , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Lisossomos/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Glândula Tireoide/metabolismo , Tireotropina/metabolismo , Transplante Homólogo
15.
Invest Ophthalmol Vis Sci ; 56(12): 7214-23, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26540660

RESUMO

PURPOSE: Cystinosis is caused by a deficiency in the lysosomal cystine transporter, cystinosin (CTNS gene), resulting in cystine crystal accumulation in tissues. In eyes, crystals accumulate in the cornea causing photophobia and eventually blindness. Hematopoietic stem progenitor cells (HSPCs) rescue the kidney in a mouse model of cystinosis. We investigated the potential for HSPC transplantation to treat corneal defects in cystinosis. METHODS: We isolated HSPCs from transgenic DsRed mice and systemically transplanted irradiated Ctns-/- mice. A year posttransplantation, we investigated the fate and function of HSPCs by in vivo confocal and fluorescence microscopy (IVCM), quantitative RT-PCR (RT-qPCR), mass spectrometry, histology, and by measuring the IOP. To determine the mechanism by which HSPCs may rescue disease cells, we transplanted Ctns-/- mice with Ctns-/- DsRed HSPCs virally transduced to express functional CTNS-eGFP fusion protein. RESULTS: We found that a single systemic transplantation of wild-type HSPCs prevented ocular pathology in the Ctns-/- mice. Engraftment-derived HSPCs were detected within the cornea, and also in the sclera, ciliary body, retina, choroid, and lens. Transplantation of HSPC led to substantial decreases in corneal cystine crystals, restoration of normal corneal thickness, and lowered IOP in mice with high levels of donor-derived cell engraftment. Finally, we found that HSPC-derived progeny differentiated into macrophages, which displayed tunneling nanotubes capable of transferring cystinosin-bearing lysosomes to diseased cells. CONCLUSIONS: To our knowledge, this is the first demonstration that HSPCs can rescue hereditary corneal defects, and supports a new potential therapeutic strategy for treating ocular pathologies.


Assuntos
Cistinose/terapia , Oftalmopatias/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Animais , Células Cultivadas , Cistinose/genética , Modelos Animais de Doenças , Oftalmopatias/congênito , Oftalmopatias/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
16.
Nefrologia ; 35(3): 304-21, 2015.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-26523297

RESUMO

INTRODUCTION: Cystinosis is a rare lysosomal systemic disease that mainly affects the kidney and the eye. Patients with cystinosis begin renal replacement therapy during the first decade of life in absence of treatment. Prognosis of cystinosis depends on early diagnosis, and prompt starting and good compliance with cysteamine treatment. Kidney disease progression, extra-renal complications and shorter life expectancy are more pronounced in those patients that do not follow treatment. The objective of this work was to elaborate recommendations for the comprehensive care of cystinosis and the facilitation of patient transition from paediatric to adult treatment, based on clinical experience. The goal is to reduce the impact of the disease, and to improve patient quality of life and prognosis. METHODS: Bibliographic research and consensus meetings among a multidisciplinary professional team of experts in the clinical practice, with cystinotic patients (T-CiS.bcn group) from 5 hospitals located in Barcelona. RESULTS: This document gathers specific recommendations for diagnosis, treatment and multidisciplinary follow-up of cystinotic patients in the following areas: nephrology, dialysis,renal transplant, ophthalmology, endocrinology, neurology, laboratory, genetic counselling,nursing and pharmacy. CONCLUSIONS: A reference document for the comprehensive care of cystinosis represents a support tool for health professionals who take care of these patients. It is based on the following main pillars: (a) a multi-disciplinary approach, (b) appropriate disease monitoring and control of intracellular cystine levels in leukocytes, (c) the importance of adherence to treatment with cysteamine, and (d) the promotion of patient self-care by means of disease education programmes. All these recommendations will lead us, in a second phase, to create a coordinated transition model between paediatric and adult care services which will contemplate the specific needs of cystinosis.


Assuntos
Assistência Integral à Saúde/normas , Cistinose/terapia , Transição para Assistência do Adulto/normas , Adolescente , Adulto , Sistemas de Transporte de Aminoácidos Neutros/deficiência , Sistemas de Transporte de Aminoácidos Neutros/genética , Doenças da Córnea/diagnóstico , Doenças da Córnea/etiologia , Doenças da Córnea/terapia , Cisteamina/uso terapêutico , Cistinose/complicações , Cistinose/diagnóstico , Cistinose/genética , Gerenciamento Clínico , Diagnóstico Precoce , Doenças do Sistema Endócrino/diagnóstico , Doenças do Sistema Endócrino/etiologia , Doenças do Sistema Endócrino/terapia , Aconselhamento Genético , Humanos , Comunicação Interdisciplinar , Falência Renal Crônica/etiologia , Falência Renal Crônica/prevenção & controle , Falência Renal Crônica/terapia , Transplante de Rim , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/terapia , Educação de Pacientes como Assunto , Qualidade de Vida , Autocuidado
17.
Nephrol Ther ; 11(3): 152-9, 2015 Jun.
Artigo em Francês | MEDLINE | ID: mdl-25769364

RESUMO

Cystinosis is a multisystemic autosomal recessive disorder characterized by an intra-lysosomal accumulation of cystine. It is due to a defect of cystine transport through the membrane of the lysosome. The classical infantile form is characterized by a proximal tubulopathy, corneal cystine crystals and progressive renal failure, leading to end stage renal disease before 20 years of age in 90% of cases in historical cohorts. It is the most common cause of Fanconi syndrome in children. Due to recent progress in renal transplantation and to the specific treatment with cysteamine, patients survival improved significantly in the last years and adult nephrologists take care of such patients. However, disease evolution is characterized by other complications: endocrinological (hypothyroidism, diabetes, male hypogonadism), neuromuscular and of the central nervous system. Cysteamine delays the onset of these complications. A multidisciplinary team should take care of these patients, even if the nephrologist remains in first line. Apart from infantile form, there is a juvenile form, with a later onset, and an adult form, which may be only ocular, although renal involvement may be associated. The aim of this revue is to summarize actual knowledge of the disease to provide guidance to adult nephrologist to take care of his patients.


Assuntos
Cistinose , Adolescente , Adulto , Cisteamina/uso terapêutico , Eliminadores de Cistina/uso terapêutico , Cistinose/complicações , Cistinose/tratamento farmacológico , Cistinose/fisiopatologia , Cistinose/terapia , Síndrome de Fanconi/etiologia , Síndrome de Fanconi/prevenção & controle , Humanos , Falência Renal Crônica/etiologia , Transplante de Rim , Insuficiência Renal/etiologia
20.
Stem Cells ; 33(1): 301-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25186209

RESUMO

Despite controversies on the potential of hematopoietic stem cells (HSCs) to promote tissue repair, we previously showed that HSC transplantation could correct cystinosis, a multisystemic lysosomal storage disease, caused by a defective lysosomal membrane cystine transporter, cystinosin (CTNS gene). Addressing the cellular mechanisms, we here report vesicular cross-correction after HSC differentiation into macrophages. Upon coculture with cystinotic fibroblasts, macrophages produced tunneling nanotubes (TNTs) allowing transfer of cystinosin-bearing lysosomes into Ctns-deficient cells, which exploited the same route to retrogradely transfer cystine-loaded lysosomes to macrophages, providing a bidirectional correction mechanism. TNT formation was enhanced by contact with diseased cells. In vivo, HSCs grafted to cystinotic kidneys also generated nanotubular extensions resembling invadopodia that crossed the dense basement membranes and delivered cystinosin into diseased proximal tubular cells. This is the first report of correction of a genetic lysosomal defect by bidirectional vesicular exchange via TNTs and suggests broader potential for HSC transplantation for other disorders due to defective vesicular proteins.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Lisossomos/metabolismo , Macrófagos/citologia , Nanotubos , Animais , Cistinose/metabolismo , Cistinose/patologia , Cistinose/terapia , Fibroblastos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
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