Clinical aspects of autosomal recessive polycystic kidney disease

INTRODUÇÃO: A Doença Renal Policística Autossômica Recessiva (DRPAR) é uma causa importante de morbidade e mortalidade pediátricas, com um espectro variável de manifestações clínicas. MÉTODOS: A apresentação e evolução clínica de 25 pacientes (Pts) foram analisadas através da revisão de prontuários, aplicando-se os formulários propostos por Guay-Woodford et al. As morbidades associadas à doença foram avaliadas quanto à frequência e à idade de manifestação. RESULTADOS: A idade média de diagnóstico foi de 61,45 meses (0 a 336,5 meses), com distribuição similar entre os sexos (52% dos pts do sexo feminino). Houve histórico familiar da doença em 20% dos casos (5/25), com dois casos de consanguinidade. Na análise inicial, diagnosticou-se hipertensão arterial (HAS) em 56% dos Pts (14/25); doença renal crônica estágio > 2 (DRC > 2) em 24% (6/25); infecções do trato urinário (ITU) em 40% (10/25) e hipertensão portal (HP) em 32% dos casos (8/25). Das ultrassonografias abdominais iniciais, 80% demonstraram rins ecogênicos com cistos grosseiros e 64% detectaram fígado e vias biliares normais. Inibidores da ECA foram utilizados em 36% dos Pts, betabloqueadores em 20%, bloqueadores de canais de cálcio em 28% e diuréticos em 36% dos casos. Na análise final, após um tempo de acompanhamento médio de 152,2 meses (29,8 a 274,9 meses), HAS foi diagnosticada em 76% dos Pts, DRC > 2 em 44%, ITU em 52% e HP em 68%. CONCLUSÃO: As altas morbidade e mortalidade associadas à DRPAR justificam a construção de um banco de dados internacional, visando ao estabelecimento de um tratamento de suporte precoce.INTRODUCTION: Autosomal Recessive Polycystic Kidney Disease (ARPKD) is an important pediatric cause of morbidity and mortality, with a variable clinical spectrum. METHODS: The clinical presentation and evolution of 25 patients (Pts) were analyzed by clinical record review, according to the forms proposed by Guay-Woodford et al. Morbidities associated with the disease were evaluated with respect to their frequencies and age of onset. RESULTS: The median age at the diagnosis was 61.45 months (0 to 336.5 months), with similar gender distribution (52% of the patients were female). A family ARPKD history was found in 20% of the cases (5/25), two of them associated with consanguinity. On arrival, arterial hypertension (SAH) was diagnosed in 56% of the Pts (14/25); chronic kidney disease stage > 2 (CKD > 2) in 24% (6/25); urinary tract infection (UTI) in 40% (10/25); and portal hypertension (PH) in 32% of the cases (8/25). Eighty percent of the initial abdominal ultrasonograms detected echogenic kidneys with gross cysts and 64% demonstrated normal liver and biliary ducts. ACE inhibitors were used in 36% of the analyzed patients, beta-blockers in 20%, calcium channel blockers in 28%, and diuretics in 36% of them. In the final evaluation, after an average follow-up time of 152.2 months (29.8 to 274.9 months), SAH was detected in 76% of the cases, CKD > 2 in 44%, UTI in 52% and PH in 68%. CONCLUSION: The high morbidity and mortality associated with ARPKD justify the assembly of an international database, with the aim of establishing an early therapeutic support

Bases moleculares e celulares das nefropatias hereditárias císticas

The inherited cystic nephropathies (ICNs) are caused by gene mutations determinant to the development of renal epithelial cell abnormalities, alterations that create the biological conditions necessary to cyst formation. The identification of genes mutated in these diseases and the characterization of their protein products have been allowing the elucidation of mechanisms involved in their pathogenesis. The current review focus on the genetic basis and molecular pathogenesis of such illnesses, though it also briefly addresses clinical and epidemiological aspects of the ICNs with higher medical and socioeconomical impact. Within this disease set, we will approach autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, nephronophthises, autosomal dominant tubule-interstitial kidney disease, von Hippel-Lindau disease, and tuberous sclerosis complex. These ICNs present overlapping of clinical manifestations and share pathways and molecular defects. Among their common features, we will focus on the central role of abnormalities affecting the primary apical cilium and intracellular signaling pathways responsible for fundamental alterations in cell phenotype. When highlighting the advances in molecular and cellular pathogenesis of ICNs, we will critically discuss the establishment, the roles and the implications of the defective cytosolic calcium homeostasis; hyperproliferative cell response to cyclic AMP; high cell proliferation and apoptosis rates; extracellular matrix alterations; cell polarity abnormalities; and transepithelial fluid secretion. The knowledge accumulated in the last two decades brought a new molecular and cellular scenario to the ICNs, creating the required platform to develop preclinical assays. Such studies, in turn, have been supporting the performance of robust clinical trials which have been opening promising therapeutic perspectives.As nefropatias hereditárias císticas (NHCs) são causadas por mutações gênicas determinantes ao desenvolvimento de anormalidades nas células renais epiteliais, alterações que criam as condições biológicas necessárias à formação cística. A identificação de genes mutados nessas enfermidades e a caracterização de seus produtos proteicos vêm permitindo a elucidação de mecanismos envolvidos em sua patogênese. Esta revisão tem como foco as bases genéticas e a patogênese molecular dessas enfermidades, embora também aborde brevemente aspectos clínicos e epidemiológicos das NHCs de maior impacto médico e socioeconômico. Dentro deste conjunto de moléstias, abordaremos a doença renal policística autossômica dominante, doença renal policística autossômica recessiva, nefronoftises, doença renal túbulo-intersticial autossômica dominante, doença de von Hippel-Lindau e complexo esclerose tuberosa. Essas NHCs possuem sobreposição de manifestações clínicas e compartilham vias e defeitos moleculares. Entre suas características comuns, destacaremos o papel central de anormalidades no cílio apical primário e de vias de sinalização intracelular responsáveis por alterações fundamentais do fenótipo celular. Ao apresentar os avanços obtidos na patogênese molecular e celular das NHCs, discutiremos criticamente o estabelecimento, os papeis e as implicações da homeostase defeituosa de cálcio citosólico; resposta celular hiperproliferativa ao AMP cíclico; taxas elevadas de proliferação celular e apoptose; alterações da matriz extracelular; alterações da polaridade celular; e secreção transepitelial de fluido. O conhecimento acumulado nas últimas duas décadas trouxe um novo contexto molecular e celular às NHCs, capaz de criar a plataforma de conhecimento necessária para o desenvolvimento de ensaios pré-clínicos. Tais ensaios, por sua vez, vêm amparando a condução de estudos clínicos robustos, os quais têm aberto perspectivas terapêuticas promissoras

Cell therapy perspectives in neurology

Neste artigo de revisão, buscamos ressaltar alguns dos avanços mais recentes na pesquisa sobre células-tronco em neurologia. Além disso, buscamos demonstrar a direta associação entre seu funcionamento e mecanismos de replicação, diferenciação e maturação, além da terapêutica celular de algumas doenças neurológicas. Abordamos a provável associação entre essas células indiferenciadas e a origem de alguns tumores malignos do SNC, bem como os potenciais terapêuticos que o transplante das mesmas tem na medicina neurológica regenerativa. Por fim, concluímos que o entendimento e a pesquisa sobre esses mecanismos podem abrir portas para abordagens mais diretas e eficazes de diversas doenças atualmente incuráveis do sistema nervoso.In this review, we sought to highlight some of the latest advances in stem-cell research in neurology. In addition, we demonstrated the direct association between its functioning and replication mechanisms, differentiation and maturation, and also the cell therapy involved in some neurological diseases. We discussed the possible association between these undifferentiated cells and the source of some malignant tumors of the CNS, as well as the therapeutic potential of transplanting these cells in neurologic regenerative medicine. Finally, we conclude that the understanding and research on these mechanisms may lead the way to more direct and effective approaches of several currently incurable diseases of the nervous system

Exploring the Free Energy Landscape: From Dynamics to Networks and Back

The knowledge of the Free Energy Landscape topology is the essential key to understand many biochemical processes. The determination of the conformers of a protein and their basins of attraction takes a central role for studying molecular isomerization reactions. In this work, we present a novel framework to unveil the features of a Free Energy Landscape answering questions such as how many meta-stable conformers are, how the hierarchical relationship among them is, or what the structure and kinetics of the transition paths are. Exploring the landscape by molecular dynamics simulations, the microscopic data of the trajectory are encoded into a Conformational Markov Network. The structure of this graph reveals the regions of the conformational space corresponding to the basins of attraction. In addition, handling the Conformational Markov Network, relevant kinetic magnitudes as dwell times or rate constants, and the hierarchical relationship among basins, complete the global picture of the landscape. We show the power of the analysis studying a toy model of a funnel-like potential and computing efficiently the conformers of a short peptide, the dialanine, paving the way to a systematic study of the Free Energy Landscape in large peptides.Comment: PLoS Computational Biology (in press

Brazilian consortium for the study on renal diseases associated with COVID-19 : a multicentric effort to understand SARS-CoV-2-related nephropathy

Kidney involvement appears to be frequent in coronavirus disease 2019 (COVID-19). Despite this, information concerning renal involvement in COVID-19 is still scarce. Several mechanisms appear to be involved in the complex relationship between the virus and the kidney. Also, different morphological patterns have been described in the kidneys of patients with COVID-19. For some authors, however, this association may be just a coincidence. To investigate this issue, we propose assessing renal morphology associated with COVID-19 at the renal pathology reference center of federal university hospitals in Brazil. Data will come from a consortium involving 17 federal university hospitals belonging to Empresa Brasileira de Serviços Hospitalares (EBSERH) network, as well as some state hospitals and an autopsy center. All biopsies will be sent to the referral center for renal pathology of the EBSERH network. The data will include patients who had coronavirus disease, both alive and deceased, with or without pre-existing kidney disease. Kidney biopsies will be analyzed by light, fluorescence, and electron microscopy. Furthermore, immunohistochemical (IHC) staining for various inflammatory cells (i.e., cells expressing CD3, CD20, CD4, CD8, CD138, CD68, and CD57) as well as angiotensin-converting enzyme 2 (ACE2) will be performed on paraffinized tissue sections. In addition to ultrastructural assays, in situ hybridization (ISH), IHC and reverse transcription-polymerase chain reaction (RT-PCR) will be used to detect Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) in renal tissue. For the patients diagnosed with Collapsing Glomerulopathy, peripheral blood will be collected for apolipoprotein L-1 (APOL1) genotyping. For patients with thrombotic microangiopathy, thrombospondin type 1 motif, member 13 (ADAMTS13), antiphospholipid, and complement panel will be performed. The setting of this study is Brazil, which is second behind the United States in highest confirmed cases and deaths. With this complete approach, we hope to help define the spectrum and impact, whether immediate or long-term, of kidney injury caused by SARS-CoV-2

Contributions of genetically-modified animal models to the understanding and intervention in autosomal dominant polycystic kidney disease: present and future

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic renal disease, representing the fourth cause of end-stage kidney disease. This disorder occurs due to mutations in the PKD1 (Polycystic Kidney Disease 1) or PKD2 (Polycystic Kidney Disease 2) genes, with most of the cases caused by mutations in PKD1. The products of these genes, polycystin-1 (PC1) and polycystin-2 (PC2), are integral membrane glycoproteins that form a complex expressed in the surface of primary apical cilia of several cells, including renal tubular cells. Such proteins are also expressed in other subcellular sites. PC2 functions as a non-selective cation channel with high permeability to calcium, while PC1 is thought to function as a membrane receptor and likely as an adhesion molecule. Since the discovery and characterization of PKD1 and PKD2, the generation of genetically-modified animal models has prompted remarkable advances in the elucidation of ADPKD pathogenesis and identification of potential therapeutic targets. Such animals included knockout, knockin and spatial and temporal conditional knockout models. These progresses allowed the recognition of a complex genetic network involved in the modulation of polycystic kidney disease and the identification of potential modifiers of ADPKD. The mentioned advances also allowed the performance of strategic preclinical studies in mouse models orthologous to this disease, creating appropriate platforms to support robust clinical trials. The generation of composed mutants will likely lead to progressively more complex and specific analyses of ADPKD pathogenesis in the next decades, with meaningful clinical consequences. Moreover, the technical complexity and speed of generating strategic genetically-modified animal models has dramatically improved in recent years, considerably expanding the possibilities for the coming future. In addition, recently developed in vitro approaches such as induced pluripotent stem cells, kidney-on-a-chip and kidney organoid technologies are thought to bring robust and complementary future inputs to the understanding and therapy directed to ADPKD