RESUMO
Multi-organ fibrosis among end stage renal disease (ESRD) patients cannot be explained by uremia alone. Despite mitigation of thrombosis during hemodialysis (HD), subsequent platelet dysfunction and tissue dysregulation are less understood. We comprehensively profiled plasma and platelets from ESRD patients before and after HD to examine HD-modulation of platelets beyond thrombotic activation. Basal plasma levels of proteolytic regulators and fibrotic factors were elevated in ESRD patients compared to healthy controls, with isoform-specific changes during HD. Platelet lysate (PL) RNA transcripts for growth and coagulative factors were elevated post-HD, with upregulation correlated to HD vintage. Platelet secretome correlations to plasma factors reveal acutely induced pro-fibrotic platelet phenotypes in ESRD patients during HD characterized by preferentially enhanced proteolytic enzyme translation and secretion, platelet contribution to inflammatory response, and increasing platelet dysfunction with blood flow rate (BFR) and Vintage. Compensatory mechanisms of increased platelet growth factor synthesis with acute plasma matrix metalloproteinase (MMP) and tissue inhibitor of MMPs (TIMP) increases show short-term mode-switching between dialysis sessions leading to long-term pro-fibrotic bias. Chronic pro-fibrotic adaptation of platelet synthesis were observed through changes in differential secretory kinetics of heterogenous granule subtypes. We conclude that chronic and acute platelet responses to HD contribute to a pro-fibrotic milieu in ESRD.
Assuntos
Plaquetas/metabolismo , Fibrose/etiologia , Fibrose/metabolismo , Proteólise , Diálise Renal/efeitos adversos , Biomarcadores , Velocidade do Fluxo Sanguíneo , Suscetibilidade a Doenças , Humanos , Mediadores da Inflamação/metabolismo , Metaloproteinases da Matriz/sangue , Metaloproteinases da Matriz/metabolismo , Diálise Renal/métodos , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-1/metabolismoRESUMO
PURPOSE: Cardiac native-T1 times have correlated to extracellular volume fraction in patients with confirmed fibrosis. However, whether other factors that can occur either alongside or independently of fibrosis including increased intracellular water volume, altered magnetization transfer (MT), or glycation of hemoglobin, lengthen T1 times in the absence of fibrosis remains unclear. The current study examined whether native-T1 times are elevated in hypertrophic diabetics with elevated hemoglobin A1C (HbA1c) without diffuse fibrosis. METHODS: Native-T1 times were quantified in 27 diabetic and 10 healthy adults using a modified Look-Locker imaging (MOLLI) sequence at 1.5â¯T. The MT ratio (MTR) was quantified using dual flip angle cine balanced steady-state free precession. Gadolinium (0.2â¯mmol/kg Gd-DTPA) was administered as a bolus and post-contrast T1-times were quantified after 15â¯min. Means were compared using a two-tailed student's t-test, while correlations were assessed using Pearson's correlations. RESULTS: While left ventricular volumes, ejection fraction, and cardiac output were similar between groups, left ventricular mass and mass-to-volume ratio (MVR) were significantly higher in diabetic adults. Mean ECV (0.25⯱â¯0.02 Healthy vs. 0.25⯱â¯0.03 Diabetic, Pâ¯=â¯0.47) and MTR (125⯱â¯16% Healthy vs. 125⯱â¯9% Diabetic, Pâ¯=â¯0.97) were similar, however native-T1 times were significantly higher in diabetics (1016⯱â¯21â¯ms Healthy vs. 1056⯱â¯31â¯ms Diabetic, Pâ¯=â¯0.00051). Global native-T1 times correlated with MVR (ρâ¯=â¯0.43, Pâ¯=â¯0.008) and plasma HbA1c levels (ρâ¯=â¯0.43, Pâ¯=â¯0.0088) but not ECV (ρâ¯=â¯0.06, Pâ¯=â¯0.73). Septal native-T1 times correlated with septal wall thickness (ρâ¯=â¯0.50, Pâ¯=â¯0.001). CONCLUSION: In diabetic adults with normal ECV values, elevated native-T1 times may reflect increased intracellular water volume and changes secondary to increased hemoglobin glycation.