Avaliação dos fatores de risco de aterosclerose e disfunção endotelial em pacientes com glomerulopatias primárias
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2019-11-25
Autores
Hagemann, Rodrigo
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Universidade Estadual Paulista (Unesp)
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Introdução: Glomerulopatias cursam em diferentes formas de apresentação clínica e laboratorial, podendo ser classificadas como primárias ou secundárias e são a terceira causa de doença renal crônica (DRC) com necessidade de diálise no Brasil. Distúrbio mineral e ósseo (DMO) é uma das complicações da DRC e está presente já nos estágios iniciais, quando as concentrações séricas de fosfato e de hormônio da paratireoide (PTH) podem ainda estar normais, porém já há aumento da concentração sérica do fator de crescimento de fibroblasto (FGF) 23. Essa instalação precoce do DMO contribui para aumento do risco cardiovascular. O processo de aterosclerose é uma resposta inflamatória a uma série de agressores, conhecidos como fatores de risco, classificados em tradicionais e não tradicionais. Os pacientes com glomerulopatias primárias estão expostos a uma série desses fatores, formando um grupo bastante heterogêneo. A avaliação da espessura médio-intimal de carótidas (EMIC) e da vasodilatação fluxo-mediada (VFM) são maneiras não invasivas de avaliação do risco cardiovascular. Hipótese: Pacientes com glomerulopatias primárias apresentam alta prevalência de aterosclerose e disfunção endotelial, não explicada totalmente pelos fatores de risco tradicionais, mas provavelmente influenciada pela instalação precoce do DMO. Objetivo geral: Avaliar os principais marcadores de aterosclerose em pacientes portadores de glomerulopatias primárias, incluindo os fatores de risco não tradicionais. Método: Estudo clínico, observacional, transversal e controlado. Foram incluídos portadores de glomerulopatia primária e excluídos os menores de 18 anos de idade, as gestantes, aqueles com menos de três meses de seguimento e os com glomerulopatia secundária. Também foram excluídos aqueles que, no momento da coleta, apresentavam proteinúria maior que 6 gramas/24 horas e uso de prednisona em doses superiores a 0,2 mg/kg/dia. Os pacientes foram submetidos à avaliação clínica, nutricional, laboratorial e ultrassonográfica. Foi utilizado um grupo controle histórico, formado por doadores de sangue e utilizado análise por agrupamento, para definir fenótipos de pacientes. Resultados: Foram atendidos 378 pacientes entre março de 2016 e novembro de 2017. Destes, 95 foram incluídos, 88 colheram os exames, um foi excluído e 23 não realizaram a ultrassonografia. Os pacientes com glomerulopatia apresentaram maior EMIC média em relação ao controle (0,66 versus 0,60), p=0,003. Após análise multivariada, mantiveram relevância estatística a idade e os valores de pressão arterial sistólica (PAS). O grupo glomerulopatia não apresentou diferença nos parâmetros avaliados em relação à mediana de FGF-23 (252,79). Análise de correlações mostrou relação entre idade e EMIC média (r=0,607; p<0,01), PAS e EMIC média (r=0,388; p=0,002), índice de massa corpórea (IMC) e VFM (r= -0,262; p=0,036), taxa de filtração glomerular (TFG) e EMIC média (r=-0,247; p=0,049), TFG e VFM (r=0,317; p=0,011), tempo de seguimento e EMIC média (r=0,312; p=0,012), tempo de HAS e VFM (r= -0,262; p=0,036); ácido úrico e VFM (r=-0,347; p=0,005), glicemia e EMIC média (r=0,3882; p=0,002) e triglicérides e VFM (r=-0,425; p<0,001). Após análise multivariada, mantiveram relevância estatística apenas EMIC média e idade, VFM e TFG e VFM e ácido úrico. A análise de agrupamento revela pacientes em 5 clusters e associou maior EMIC aos idosos. No cluster da DRC teve suas consequências, como hiperfosfatemia, hiperhomocisteínemia e anemia, além do maior número de diabéticos. Outro agrupamento mostrou uma maior excreção de sódio, maior porcentagem de tabagistas e maior concentração sérica de FGF-23 culminando em disfunção endotelial e um comportamento intrigante foi observado no conjunto de homens, jovens, com hiperuricemia e alto valor de fósforo urinário no contexto da hipovitaminose D, possivelmente implicada na disfunção endotelial. Ainda vimos que o cluster mais representativo mostra o espectro de um grupo “protegido”, diante de dois aspectos, ser constituído por mulheres (82%) e com as maiores concentrações de HDL colesterol. Discussão e conclusão: Os pacientes com glomerulopatias primárias apresentaram maior risco cardiovascular, marcado por uma maior EMIC. Entretanto, esse risco não foi claramente explicitado pelo DMO precoce. Isso pode ser decorrente da grande heterogeneidade de valores séricos do FGF-23 e/ou dos desfechos utilizados no presente estudo não serem os mais adequados para sua avaliação. Entre os fatores de risco não tradicionais nessa população, apenas a DRC mostrou relevância estatística. São necessário estudos clínicos, randomizados e de intervenção para melhor avaliação da PAS e da concentração sérica de ácido úrico nesses pacientes. Até o nosso conhecimento, trata-se do primeiro estudo que avaliou DMO precoce em pacientes com glomerulopatias primárias e primeiro que realizou análise de agrupamento para esta população
Introduction: Glomerulonephritis can present in different clinical and laboratory ways, can be classified as primary or secondary and are the third cause of chronic kidney disease (CKD) requiring dialysis in Brazil. Mineral and bone disorder (MBD) is one of the CKD complications and is already present in the early stages of the disease. At these stages, serum phosphate and parathyroid hormone (PTH) concentrations may still be normal, but there is an increase in serum concentration of fibroblast growth factor (FGF) 23. This early onset of MBD contributes to increase cardiovascular risk. Atherosclerosis is an inflammatory response of the endothelium to a number of aggressors, known as risk factors, classified into traditional and nontraditional. Patients with primary glomerulonephritis are exposed to a number of these factors, composing a heterogeneous group. Evaluation of carotid intima-media thickness (CIMT) and flow-mediated vasodilation (FMV) are noninvasive ways of assessing cardiovascular risk. Hypothesis: There is a high prevalence of atherosclerosis and endothelial dysfunction in patients with primary glomerulonephritis not totally explained by traditional risk factors, but probably influenced by early onset of MBD. Objective: Evaluate the markers of atherosclerosis in patients with primary glomerulonephritis, including nontraditional risk factors. Method: Clinical, observational, cross-sectional and controlled study that included patients with primary glomerulonephritis. Patients under 18 years-old, with secondary glomerulonephritis, pregnant women and with less than three months of follow-up were excluded. Patients with proteinuria higher than 6 grams/24 hours and in use of prednisone in doses higher than 0,2 mg/kg/day in the last three months also were excluded. The patients underwent clinical, nutritional, laboratory and ultrasound evaluation. A historical control group of blood donors was used and cluster analysis was used to define patient phenotypes. Results: Between March 2016 and November 2017, 378 outpatients were followed. Of these, 95 were included, 88 collected the exams, one was excluded and 23 did not undergo ultrasound exam. Patients with glomerulonephritis had higher mean CIMT than control group (0.66 versus 0.60), p = 0.003. After multivariate analysis, age and systolic blood pressure (SBP) remained statistically significant. Correlation analysis showed a relationship between age and mean CIMT (r = 0.607; p <0.01), SBP and mean CIMT (r = 0.388; p = 0.002), body mass index (BMI) and FMV (r = -0.262; p = 0.036), glomerular filtration rate (GFR) and mean CIMT (r = -0.247; p = 0.049), GFR and FMV (r = 0.317; p = 0.011), time of follow-up and mean CIMT (r = 0.312 ; p = 0.012), serum uric acid and FMV (r = -0.347; p = 0.005), serum glucose and mean CIMT (r = 0.3882; p = 0.002) and serum triglycerides and FMV (r = -0.425; p <0.001). After multivariate analysis, only mean CMIT and age, FMV and GFR and FMV and serum uric acid remained statistically significant. Cluster analysis revealed patients in 5 clusters and associated higher CIMT with the elderly. In the CKD cluster there were its consequences, such as hyperphosphataemia, hyperhomocysteinemia and anemia, in addition to the higher number of diabetics. Another group showed higher sodium excretion, higher percentage of smokers and higher serum FGF-23 concentration culminating in endothelial dysfunction and intriguing behavior was observed in the group of young men with hyperuricemia and high phosphate in urine in the context of hypovitaminosis D, possibly implicated in endothelial dysfunction. We also observed that the most representative cluster shows the spectrum of a “protected” group, being women (82%) and with the highest concentrations of HDL cholesterol. Discussion and conclusion: Patients with primary glomerulonephritis own a higher cardiovascular risk, marked by a higher CIMT. However, this increased risk was not clearly explained by early MBD. This may be due to the great heterogeneity of serum FGF-23 values and/or the outcomes used in the present study, that are not the most appropriate for its evaluation. Among nontraditional risk factors in this population, only CKD showed statistical relevance. Randomized clinical trials are necessary to show the impact of SBP and serum uric acid concentration in these patients. To our knowledge, this is the first study to evaluate early MBD in patients with primary glomerulonephritis and the first to perform cluster analysis for this population.
Introduction: Glomerulonephritis can present in different clinical and laboratory ways, can be classified as primary or secondary and are the third cause of chronic kidney disease (CKD) requiring dialysis in Brazil. Mineral and bone disorder (MBD) is one of the CKD complications and is already present in the early stages of the disease. At these stages, serum phosphate and parathyroid hormone (PTH) concentrations may still be normal, but there is an increase in serum concentration of fibroblast growth factor (FGF) 23. This early onset of MBD contributes to increase cardiovascular risk. Atherosclerosis is an inflammatory response of the endothelium to a number of aggressors, known as risk factors, classified into traditional and nontraditional. Patients with primary glomerulonephritis are exposed to a number of these factors, composing a heterogeneous group. Evaluation of carotid intima-media thickness (CIMT) and flow-mediated vasodilation (FMV) are noninvasive ways of assessing cardiovascular risk. Hypothesis: There is a high prevalence of atherosclerosis and endothelial dysfunction in patients with primary glomerulonephritis not totally explained by traditional risk factors, but probably influenced by early onset of MBD. Objective: Evaluate the markers of atherosclerosis in patients with primary glomerulonephritis, including nontraditional risk factors. Method: Clinical, observational, cross-sectional and controlled study that included patients with primary glomerulonephritis. Patients under 18 years-old, with secondary glomerulonephritis, pregnant women and with less than three months of follow-up were excluded. Patients with proteinuria higher than 6 grams/24 hours and in use of prednisone in doses higher than 0,2 mg/kg/day in the last three months also were excluded. The patients underwent clinical, nutritional, laboratory and ultrasound evaluation. A historical control group of blood donors was used and cluster analysis was used to define patient phenotypes. Results: Between March 2016 and November 2017, 378 outpatients were followed. Of these, 95 were included, 88 collected the exams, one was excluded and 23 did not undergo ultrasound exam. Patients with glomerulonephritis had higher mean CIMT than control group (0.66 versus 0.60), p = 0.003. After multivariate analysis, age and systolic blood pressure (SBP) remained statistically significant. Correlation analysis showed a relationship between age and mean CIMT (r = 0.607; p <0.01), SBP and mean CIMT (r = 0.388; p = 0.002), body mass index (BMI) and FMV (r = -0.262; p = 0.036), glomerular filtration rate (GFR) and mean CIMT (r = -0.247; p = 0.049), GFR and FMV (r = 0.317; p = 0.011), time of follow-up and mean CIMT (r = 0.312 ; p = 0.012), serum uric acid and FMV (r = -0.347; p = 0.005), serum glucose and mean CIMT (r = 0.3882; p = 0.002) and serum triglycerides and FMV (r = -0.425; p <0.001). After multivariate analysis, only mean CMIT and age, FMV and GFR and FMV and serum uric acid remained statistically significant. Cluster analysis revealed patients in 5 clusters and associated higher CIMT with the elderly. In the CKD cluster there were its consequences, such as hyperphosphataemia, hyperhomocysteinemia and anemia, in addition to the higher number of diabetics. Another group showed higher sodium excretion, higher percentage of smokers and higher serum FGF-23 concentration culminating in endothelial dysfunction and intriguing behavior was observed in the group of young men with hyperuricemia and high phosphate in urine in the context of hypovitaminosis D, possibly implicated in endothelial dysfunction. We also observed that the most representative cluster shows the spectrum of a “protected” group, being women (82%) and with the highest concentrations of HDL cholesterol. Discussion and conclusion: Patients with primary glomerulonephritis own a higher cardiovascular risk, marked by a higher CIMT. However, this increased risk was not clearly explained by early MBD. This may be due to the great heterogeneity of serum FGF-23 values and/or the outcomes used in the present study, that are not the most appropriate for its evaluation. Among nontraditional risk factors in this population, only CKD showed statistical relevance. Randomized clinical trials are necessary to show the impact of SBP and serum uric acid concentration in these patients. To our knowledge, this is the first study to evaluate early MBD in patients with primary glomerulonephritis and the first to perform cluster analysis for this population.
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Palavras-chave
glomerulonefrite, doença renal crônica, distúrbio mineral e ósseo, doenças cardiovasculares, glomerulonephritis, chronic kidney disease, mineral and bone disorder, cardiovascular diseases