Análise do perfil proteômico urinário de pacientes pediátricos candidatos a transplante renal por insuficiência renal terminal secundária a refluxo vesicoureteral primário
Data
2024-10-14
Orientadores
Aguiar, Wilson Ferrreira 
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
O refluxo vesicoureteral é uma malformação que pode ser identificada em cerca de 1% da população e, felizmente em sua maior parte terá um curso benigno, mantendo os acometidos assintomáticos ou mesmo sem sequelas a função renal. Entretanto, alguns pacientes evoluem a nefropatia de refluxo, podendo esta representar até 25% das causas de insuficiência renal na população pediátrica. Na intenção de identificar fatores de risco a progressão a perda da função renal relacionadas a presença do refluxo, extensas pesquisas têm sido realizadas. São fatores de risco conhecidos na literatura e que aumentam a chance de evolução a doença renal terminal o sexo masculino, a presença de sinais de displasia renal ou cicatrizes renais, a presença de refluxo vesico ureteral bilateral de alto grau e alterações da creatinina (valores séricos acima de 0.6mg/dL) no primeiro ano de vida. Fatores que poderiam ser responsáveis por uma certa proteção renal como o uso de antibiótico profilaxia e intervenções cirúrgicas não foram capazes de interromper o curso negativo da doença. Assim, entende-se que a nefropatia de refluxo e o refluxo vesico ureteral devam ser consideradas patologias diferentes, embora possam se iniciar como a mesma malformação. Dados demográficos e amostra única de urina foram obtidas de pacientes com doença renal crônica terminal secundária a refluxo vesicoureteral primário e comparados a pacientes com refluxo vesico ureteral porém com função renal normal. Análises da associação entre variáveis qualitativas e grupo foi avaliada através do teste exato de Fisher e a comparação entre distribuições das variáveis quantitativas de acordo com o grupo foi realizada através do teste de Mann-Whitney. As comparações entre tempos foi realizada através do teste de Mann-Whitney ou teste de Kruskal-Wallis quando a variável em questão apresentou três categorias. Por meio de avaliação proteômica em urina de ambos os grupos, foram listadas as proteínas encontradas e suas intensidades de expressão comparadas. Assim, estabeleceu-se 3 tipos de achados comparativos: 1) proteínas expressas exclusivamente no grupo com insuficiência renal , 2) proteínas mais expressas no grupo pacientes e 3) proteínas inibidas no grupo pacientes ( mais expressas no grupo controle). Foram encontrados potenciais biomarcadores urinários em pacientes com nefropatia de refluxo representado pela presença de genes relacionados a via de sinalização ativa de fatores de coagulação e sistema complemento e vias de sinalização inibidas relacionadas a fatores de crescimento epidermal. Espera-se que esses achados possam contribuir na busca pela compreensão das diferenças micro fisiológicas entre esses pacientes com mesma patologia, porém com desfechos tão diferenciados, possibilitando a procura por terapias personalizadas e que possam interferir ou ao menos postergar a evolução a doença renal terminal por nefropatia de refluxo.
Vesicoureteral reflux is a malformation that can be identified in approximately 1% of the population and, fortunately, in the majority of patients it will have a benign course, being those affected asymptomatic or even without sequelae to the renal function. However, some patients can evolute to reflux nephropathy, which may represent up to 25% of the causes of renal failure in the pediatric population. In order to identify risk factors for the progression and loss of renal function related to the presence of reflux, extensive research has been carried out. Risk factors known in the literature that increase the chance of developing end-stage renal disease are male gender, the presence of renal dysplasia or renal scarring, the presence of bilateral high-grade vesicoureteric reflux and serum creatinine higher than 0,6 mg/ dL in the first year of life. Factors that could be responsible for a renal protection, such as use of continuous antibiotic prophylaxis and surgical interventions, were not able to interrupt the negative course of the disease. Therefore, it is understood that reflux nephropathy and vesicoureteral reflux should be considered different pathologies, although they are probably originated from the same malformation. Demographic data and a single urine sample were obtained from patients with endstage chronic kidney disease secondary to primary vesicoureteral reflux (patient group) and compared to patients with vesicoureteral reflux but with normal renal function ( control group). Analysis of the association between qualitative variables and group was evaluated using Fisher's exact test and the comparison between distributions of quantitative variables according to group was performed using the Mann-Whitney test. Comparisons between times were performed using the Mann-Whitney test or Kruskal-Wallis test when the variable in question presented three categories Through proteomic evaluation in urine from both groups, the proteins found were listed and their expression intensities were compared. Then, 3 types of comparative findings were established: 1) proteins expressed exclusively in the group with renal failure, 2) proteins more expressed in patients with renal failure and 3) proteins inhibited in the patient group (higher expression in the control group). Potential urinary biomarkers were found in patients with reflux nephropathy represented by genes related to the active signaling coagulation pathway factors and the complement system and inhibited in pathways related to epidermal growth factors. It is hoped that these findings can contribute to the search for understanding of the microphysiological differences between these patients with same pathology, but with such different outcomes, enabling the search for personalized therapies that could interfere or at least postpone the progression to end-stage renal disease due to reflux nephropathy.
Vesicoureteral reflux is a malformation that can be identified in approximately 1% of the population and, fortunately, in the majority of patients it will have a benign course, being those affected asymptomatic or even without sequelae to the renal function. However, some patients can evolute to reflux nephropathy, which may represent up to 25% of the causes of renal failure in the pediatric population. In order to identify risk factors for the progression and loss of renal function related to the presence of reflux, extensive research has been carried out. Risk factors known in the literature that increase the chance of developing end-stage renal disease are male gender, the presence of renal dysplasia or renal scarring, the presence of bilateral high-grade vesicoureteric reflux and serum creatinine higher than 0,6 mg/ dL in the first year of life. Factors that could be responsible for a renal protection, such as use of continuous antibiotic prophylaxis and surgical interventions, were not able to interrupt the negative course of the disease. Therefore, it is understood that reflux nephropathy and vesicoureteral reflux should be considered different pathologies, although they are probably originated from the same malformation. Demographic data and a single urine sample were obtained from patients with endstage chronic kidney disease secondary to primary vesicoureteral reflux (patient group) and compared to patients with vesicoureteral reflux but with normal renal function ( control group). Analysis of the association between qualitative variables and group was evaluated using Fisher's exact test and the comparison between distributions of quantitative variables according to group was performed using the Mann-Whitney test. Comparisons between times were performed using the Mann-Whitney test or Kruskal-Wallis test when the variable in question presented three categories Through proteomic evaluation in urine from both groups, the proteins found were listed and their expression intensities were compared. Then, 3 types of comparative findings were established: 1) proteins expressed exclusively in the group with renal failure, 2) proteins more expressed in patients with renal failure and 3) proteins inhibited in the patient group (higher expression in the control group). Potential urinary biomarkers were found in patients with reflux nephropathy represented by genes related to the active signaling coagulation pathway factors and the complement system and inhibited in pathways related to epidermal growth factors. It is hoped that these findings can contribute to the search for understanding of the microphysiological differences between these patients with same pathology, but with such different outcomes, enabling the search for personalized therapies that could interfere or at least postpone the progression to end-stage renal disease due to reflux nephropathy.
Descrição
Citação
ANFREOLI, Veridiana. Análise do perfil proteômico urinário de pacientes pediátricos candidatos a transplante renal por insuficiência renal terminal secundária a refluxo vesicoureteral primário. 2024. 114 f. Tese (Doutorado em Urologia) - Escola Paulista de Medicina, Universidade Federal de São paulo (UNIFESP), São Paulo, 2024.