RESUMO
OBJECTIVES: This study investigated whether kidney transplant donors experience increased arterial stiffness compared with the general population and how arterial stiffness changes over time. MATERIALS AND METHODS: Our study included 59 kidney transplant donors and 27 healthy volunteers. All subjects underwent cardio-ankle vascular index measurements. We studied fibroblast growth factor23, klotho, monocyte chemoattractant protein-1, N-terminal pro-B-type natriuretic peptide, indoxyl sulfate, and p-cresyl sulfate levels. RESULTS: Cardio-ankle vascular index level was higher in donors 6 to 11 years after donation (8.02 ± 0.24 m/s) than in donors 2 to 6 years after donation (7.02 ± 0.27 m/s) and healthy volunteers (6.65 ± 0.22 m/s). Cardioankle vascular index level was positively correlated with age (r = 0.382, P < .001) and levels of triglyceride (r = 0.213, P = .049), blood urea nitrogen (r = 0.263, P = .014), creatinine (r = 0.354, P = .001), calcium (r = 0.228, P = .035), indoxyl sulfate (r = 0.219, P = .042), p-cresyl sulfate (r = 0.676, P ≤ .001), and monocyte chemoattractant protein-1 (r = 0.451, P ≤ .001) and negatively correlated with estimated glomerular filtration rate (r = -0.383, P < .001). Multiple linear regression analysis revealed that age (P = .026, B = 0.244), mean arterial blood pressure (P < .001, B = 0.446), blood urea nitrogen (P = .006, B = 0.302), creatinine (P = .032, B = 0.236), estimated glomerular filtration rate (P = .003, B = -0.323), fibroblast growth factor-23 (P = .007, B = 0.294), N-terminal pro-B-type natriuretic peptide (P = .005, B = 0.304), and monocyte chemoattractant protein-1 (P ≤ .001, B = 0.434) independently predicted cardio-ankle vascular index levels. CONCLUSIONS: Even without additional risk factors, kidney donors should be followed closely for arterial stiffness and cardiovascular disease, especially in the long-term (>5 years) after kidney transplant.
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Biomarcadores , Índice Vascular Coração-Tornozelo , Mediadores da Inflamação , Transplante de Rim , Valor Preditivo dos Testes , Calcificação Vascular , Rigidez Vascular , Humanos , Masculino , Feminino , Biomarcadores/sangue , Pessoa de Meia-Idade , Transplante de Rim/efeitos adversos , Adulto , Estudos de Casos e Controles , Calcificação Vascular/sangue , Calcificação Vascular/fisiopatologia , Calcificação Vascular/etiologia , Calcificação Vascular/diagnóstico , Fatores de Tempo , Mediadores da Inflamação/sangue , Fatores de Risco , Fatores de Crescimento de Fibroblastos/sangue , Fator de Crescimento de Fibroblastos 23 , Quimiocina CCL2/sangue , Uremia/sangue , Uremia/diagnóstico , Uremia/fisiopatologia , Indicã/sangue , Resultado do Tratamento , Doadores VivosRESUMO
BACKGROUND: Chronic kidney disease presents global health challenges, with hemodialysis as a common treatment. However, non-dialyzable uremic toxins demand further investigation for new therapeutic approaches. Renal tubular cells require scrutiny due to their vulnerability to uremic toxins. METHODS: In this study, a systems biology approach utilized transcriptomics data from healthy renal tubular cells exposed to healthy and post-dialysis uremic plasma. RESULTS: Differential gene expression analysis identified 983 up-regulated genes, including 70 essential proteins in the protein-protein interaction network. Modularity-based clustering revealed six clusters of essential proteins associated with 11 pathological pathways activated in response to non-dialyzable uremic toxins. CONCLUSIONS: Notably, WNT1/11, AGT, FGF4/17/22, LMX1B, GATA4, and CXCL12 emerged as promising targets for further exploration in renal tubular pathology related to non-dialyzable uremic toxins. Understanding the molecular players and pathways linked to renal tubular dysfunction opens avenues for novel therapeutic interventions and improved clinical management of chronic kidney disease and its complications.
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Túbulos Renais , Insuficiência Renal Crônica , Biologia de Sistemas , Toxinas Urêmicas , Humanos , Insuficiência Renal Crônica/sangue , Biologia de Sistemas/métodos , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Toxinas Urêmicas/metabolismo , Diálise Renal/efeitos adversos , Diálise Renal/métodos , Mapas de Interação de Proteínas , Uremia/sangue , Uremia/metabolismo , TranscriptomaRESUMO
INTRODUCTION: Combined hemodialysis (HD) and hemadsorption (HA) therapy has shown the highest clearance rates for middle and large-sized uremic toxin molecules and reduced mortality rates among maintenance HD (MHD) patients. This study aimed to investigate the effectiveness of combined HD and HA therapy in patients undergoing MHD. METHODS: Forty patients with end-stage renal disease (ESRD) were divided into three groups: HD only (14), HD + biweekly HA (14), and HD + weekly HA (12). The duration of the study was 8 weeks. Uremic toxins (ß2-microglobulin, leptin, parathyroid hormone), inflammatory markers (interleukin-6, C-reactive protein), and symptoms (appetite, pruritus, sleep quality) were assessed before the start and at the completion of therapy. Changes in the parameters were compared between the three groups. Mean differences of parameters in each group were also compared between before and after therapy. RESULTS: Decrease in BUN level (-61.34 mg/dL [95% CI: -71.33 to -51.34], p < 0.0001) and pruritus score (-3.93 [95% CI: -6.89 to -0.97], p = 0.013) was significantly larger in HD + biweekly HA group compared to the others. Only HD + biweekly HA group showed significant reductions in CRP level (-0.10 mg/L [95%: -0.18 to -0.01], p = 0.034), VAS appetite score (10.43 [95% CI: 4.99-15.87], p = 0.001), and pruritus score (-3.93 [95% CI: -6.89 to -0.97], p = 0.013) after therapy. Both HD + biweekly HA (-2.79 [95% CI: -4.97 to -0.60], p = 0.016) and HD + weekly HA group (-2.33 [95% CI: -4.59 to -0.08], p = 0.044) exhibited a significant improvement in sleep quality score after therapy. CONCLUSIONS: HD combined with a biweekly HA is associated with a greater reduction in BUN level and better improvement of pruritus in ESRD patients compared to HD alone. HD + biweekly HA can significantly reduce CRP levels, alleviate pruritus, improve appetite, and enhance sleep quality.
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Biomarcadores , Proteína C-Reativa , Falência Renal Crônica , Diálise Renal , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Falência Renal Crônica/terapia , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Biomarcadores/sangue , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Toxinas Urêmicas/sangue , Idoso , Adulto , Prurido/etiologia , Interleucina-6/sangue , Uremia/terapia , Uremia/sangue , Inflamação/sangue , Inflamação/etiologia , Hemoperfusão/métodos , Microglobulina beta-2/sangueRESUMO
RATIONALE & OBJECTIVE: The toxins that contribute to uremic symptoms in patients with chronic kidney disease (CKD) are unknown. We sought to apply complementary statistical modeling approaches to data from untargeted plasma metabolomic profiling to identify solutes associated with uremic symptoms in patients with CKD. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 1,761 Chronic Renal Insufficiency Cohort (CRIC) participants with CKD not treated with dialysis. PREDICTORS: Measurement of 448 known plasma metabolites. OUTCOMES: The uremic symptoms of fatigue, anorexia, pruritus, nausea, paresthesia, and pain were assessed by single items on the Kidney Disease Quality of Life-36 instrument. ANALYTICAL APPROACH: Multivariable adjusted linear regression, least absolute shrinkage and selection operator linear regression, and random forest models were used to identify metabolites associated with symptom severity. After adjustment for multiple comparisons, metabolites selected in at least 2 of the 3 modeling approaches were deemed "overall significant." RESULTS: Participant mean estimated glomerular filtration rate was 43mL/min/1.73m2, with 44% self-identifying as female and 41% as non-Hispanic Black. The prevalence of uremic symptoms ranged from 22% to 55%. We identified 17 metabolites for which a higher level was associated with greater severity of at least one uremic symptom and 9 metabolites inversely associated with uremic symptom severity. Many of these metabolites exhibited at least a moderate correlation with estimated glomerular filtration rate (Pearson's r≥0.5), and some were also associated with the risk of developing kidney failure or death in multivariable adjusted Cox regression models. LIMITATIONS: Lack of a second independent cohort for external validation of our findings. CONCLUSIONS: Metabolomic profiling was used to identify multiple solutes associated with uremic symptoms in adults with CKD, but future validation and mechanistic studies are needed. PLAIN-LANGUAGE SUMMARY: Individuals living with chronic kidney disease (CKD) often experience symptoms related to CKD, traditionally called uremic symptoms. It is likely that CKD results in alterations in the levels of numerous circulating substances that, in turn, cause uremic symptoms; however, the identity of these solutes is not known. In this study, we used metabolomic profiling in patients with CKD to gain insights into the pathophysiology of uremic symptoms. We identified 26 metabolites whose levels were significantly associated with at least one of the symptoms of fatigue, anorexia, itchiness, nausea, paresthesia, and pain. The results of this study lay the groundwork for future research into the biological causes of symptoms in patients with CKD.
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Insuficiência Renal Crônica , Uremia , Humanos , Feminino , Masculino , Uremia/complicações , Uremia/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/epidemiologia , Estudos Transversais , Pessoa de Meia-Idade , Idoso , Estudos de Coortes , Prurido/etiologia , Prurido/epidemiologia , Prurido/sangue , Fadiga/etiologia , Fadiga/sangue , Fadiga/epidemiologia , Metabolômica , Náusea/epidemiologia , Qualidade de Vida , Parestesia/etiologia , Parestesia/epidemiologia , Taxa de Filtração GlomerularRESUMO
Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Endothelial cell (EC) dysfunction is a key CKD-specific risk factor; however, the mechanisms by which uremia harms the endothelium are still unclear. We report a role for excessive neutrophil extracellular trap (NET) formation induced by uremic serum on EC injury. Level of plasma nucleosome and myeloperoxidase-DNA, established in vivo markers of NETs, as well as intracellular adhesion molecule (ICAM)-1 were measured in hemodialysis (HD) patients and healthy volunteers (HV) and their prognostic role evaluated. For in vitro studies, HV-derived neutrophils and differentiated HL-60 cells by retinoic acid were used to determine the effect of uremic serum-induced NETs on human umbilical vein EC (HUVEC). The level of in vivo NETs was significantly higher in incident HD patients compared to HV, and these markers were strongly associated with ICAM-1. Specifically, nucleosome and ICAM-1 levels were independent predictors of a composite endpoint, all-cause mortality, or vascular access failure. In vitro, HD-derived uremic serum significantly increased NET formation both in dHL-60 and isolated neutrophils compared to control serum, and these NETs decreased EC viability and induced their apoptosis. In addition, the level of ICAM-1, E-selectin and von Willebrand factor in HUVEC supernatant was significantly increased by uremic serum-induced NETs compared to control serum-induced NETs. Dysregulated neutrophil activities in the uremic milieu may play a key role in vascular inflammatory responses. The high mortality and CVD rates in ESRD may be explained in part by excessive NET formation leading to EC damage and dysfunction.
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Endotélio Vascular/patologia , Armadilhas Extracelulares/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/terapia , Uremia/patologia , Doenças Vasculares/patologia , Idoso , Estudos de Casos e Controles , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Armadilhas Extracelulares/metabolismo , Feminino , Células HL-60 , Humanos , Masculino , Insuficiência Renal Crônica/patologia , Uremia/sangue , Uremia/etiologia , Doenças Vasculares/etiologiaRESUMO
Theoretically, pancreas transplant alone in uremic (PTAU) patients could also be one of the options for those waiting for both pancreas and kidney grafts, but it has never been reported. There were 160 cases of pancreas transplant in this study, including 16% PTAU. The 5-year patient survival was 66.2% after PTAU, 94.5% after SPK, 95.8% after PAK, and 95.4% after PTA. Rejection of pancreas graft was significantly lower in PTAU group (3.8%), followed by 16.7% in pancreas after kidney transplant (PAK), 29.8% in simultaneous pancreas and kidney transplant (SPK) and 37.0% in pancreas transplant alone (PTA). Fasting blood sugar and serum HbA1c levels after PTAU were not significantly different from those by other subgroups. The 5-year death-censored pancreas graft survival was 100% after PTAU and PAK, and 97.0% after SPK and 77.9% after PTA. However, the 5-year death-uncensored pancreas graft survival was 67.0% after PTAU, 100% after PAK, 91.3% after SPK, and 74.0% after PTA. The superior graft survival in the PTAU group was achieved only if deaths with a functioning graft were censored. In conclusion, given the inferior patient survival outcome, PTAU is still not recommended unless SPK and PAK is not available. Although PTAU could be a treatment option for patients with diabetes complicated by end-stage renal disease (ESRD) in terms of surgical risks, endocrine function, and immunological and graft survival outcomes, modification of the organ allocation policies to prioritize SPK transplant in eligible patients should be the prime goal.
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Complicações do Diabetes , Sobrevivência de Enxerto , Falência Renal Crônica , Transplante de Rim , Transplante de Pâncreas , Uremia , Adolescente , Adulto , Complicações do Diabetes/sangue , Complicações do Diabetes/mortalidade , Complicações do Diabetes/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/mortalidade , Falência Renal Crônica/cirurgia , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Uremia/sangue , Uremia/mortalidade , Uremia/cirurgiaRESUMO
BACKGROUND: CKD, characterized by retained uremic solutes, is a strong and independent risk factor for thrombosis after vascular procedures . Urem ic solutes such as indoxyl sulfate (IS) and kynurenine (Kyn) mediate prothrombotic effect through tissue factor (TF). IS and Kyn biogenesis depends on multiple enzymes, with therapeutic implications unexplored. We examined the role of indoleamine 2,3-dioxygenase-1 (IDO-1), a rate-limiting enzyme of kynurenine biogenesis, in CKD-associated thrombosis after vascular injury. METHODS: IDO-1 expression in mice and human vessels was examined. IDO-1-/- mice, IDO-1 inhibitors, an adenine-induced CKD, and carotid artery injury models were used. RESULTS: Both global IDO-1-/- CKD mice and IDO-1 inhibitor in wild-type CKD mice showed reduced blood Kyn levels, TF expression in their arteries, and thrombogenicity compared with respective controls. Several advanced IDO-1 inhibitors downregulated TF expression in primary human aortic vascular smooth muscle cells specifically in response to uremic serum. Further mechanistic probing of arteries from an IS-specific mouse model, and CKD mice, showed upregulation of IDO-1 protein, which was due to inhibition of its polyubiquitination and degradation by IS in vascular smooth muscle cells. In two cohorts of patients with advanced CKD, blood IDO-1 activity was significantly higher in sera of study participants who subsequently developed thrombosis after endovascular interventions or vascular surgery. CONCLUSION: Leveraging genetic and pharmacologic manipulation in experimental models and data from human studies implicate IS as an inducer of IDO-1 and a perpetuator of the thrombotic milieu and supports IDO-1 as an antithrombotic target in CKD.
Assuntos
Indicã/fisiologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/sangue , Cinurenina/fisiologia , Terapia de Alvo Molecular , Complicações Pós-Operatórias/enzimologia , Insuficiência Renal Crônica/enzimologia , Trombose/enzimologia , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Animais , Aorta , Lesões das Artérias Carótidas/complicações , Trombose das Artérias Carótidas/etiologia , Trombose das Artérias Carótidas/prevenção & controle , Meios de Cultura/farmacologia , Indução Enzimática/efeitos dos fármacos , Retroalimentação Fisiológica , Feminino , Células HEK293 , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/deficiência , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Cinurenina/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos de Músculo Liso/efeitos dos fármacos , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Insuficiência Renal Crônica/tratamento farmacológico , Tromboplastina/metabolismo , Trombose/sangue , Trombose/etiologia , Trombose/prevenção & controle , Triptofano/metabolismo , Uremia/sangueRESUMO
Vitamin K dependent proteins (VKDP), such as hepatic coagulation factors and vascular matrix Gla protein (MGP), play key roles in maintaining physiological functions. Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification (VC), one of the major risk factors for cardiovascular morbidity and mortality. In this study we investigated how two vitamin K surrogate markers, dephosphorylated-undercarboxylated MGP (dp-ucMGP) and protein induced by vitamin K absence II (PIVKA-II), reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolopathy (CUA) and patients with atrial fibrillation or aortic valve stenosis. Through inter- and intra-cohort comparisons, we assessed the influence of vitamin K antagonist (VKA) use, vitamin K supplementation and disease etiology on vitamin K status, as well as the correlation between both markers. Overall, VKA therapy was associated with 8.5-fold higher PIVKA-II (0.25 to 2.03 AU/mL) and 3-fold higher dp-ucMGP (843 to 2642 pM) levels. In the absence of VKA use, non-renal patients with established VC have dp-ucMGP levels similar to controls (460 vs. 380 pM), while in HD and CUA patients, levels were strongly elevated (977 pM). Vitamin K supplementation significantly reduced dp-ucMGP levels within 12 months (440 to 221 pM). Overall, PIVKA-II and dp-ucMGP showed only weak correlation (r2 ≤ 0.26) and distinct distribution pattern in renal and non-renal patients. In conclusion, VKA use exacerbated vitamin K deficiency across all etiologies, while vitamin K supplementation resulted in a vascular VKDP status better than that of the general population. Weak correlation of vitamin K biomarkers calls for thoughtful selection lead by the research question. Vitamin K status in non-renal deficient patients was not anomalous and may question the role of vitamin K deficiency in the pathogenesis of VC in these patients.
Assuntos
Biomarcadores/sangue , Proteínas de Ligação ao Cálcio/sangue , Proteínas da Matriz Extracelular/sangue , Precursores de Proteínas/sangue , Calcificação Vascular/sangue , Deficiência de Vitamina K/sangue , Vitamina K/sangue , 4-Hidroxicumarinas/uso terapêutico , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/complicações , Fibrilação Atrial/sangue , Fibrilação Atrial/complicações , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Suplementos Nutricionais , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Indenos/uso terapêutico , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Protrombina , Diálise Renal/efeitos adversos , Uremia/sangue , Uremia/complicações , Calcificação Vascular/complicações , Vitamina K/antagonistas & inibidores , Vitamina K/uso terapêutico , Deficiência de Vitamina K/complicações , Proteína de Matriz GlaRESUMO
Although the clearance of low-molecular weight toxins is modulated by dialysis dose, the relationship between dialysis adequacy and middle systemic inflammatory mediators is often overlooked. Thus, the relationship between dialysis adequacy, pro- and anti-inflammatory cytokines and chemokines in hemodialysis (HD) patients was investigated. Forty-eight HD patients (19 women and 25 men) were investigated. Age, body mass index, time in HD, nutritional status, Kt/V and blood biochemical parameters was similar in patients of both sexes (P > 0.05). Thus, patients were stratified by dialysis adequacy measured by Kt/V method (adequate Kt/V ≥ 1.2). Post-HD urea, creatinine, cytokines (IFN-γ, IL-4 and IL-10) and chemokines (CCL-2, CCL-5, CXCL-8 and CXCL-10) were higher in patients with Kt/V < 1.2 (P < 0.05). Kt/V exhibited significant correlation with CXCL-10/IP-10 serum levels. Positive correlation between creatinine with IFN-γ, CCL-2/MCP-1, and CXCL-10/IP-10, and negative correlation with IL-10 was identified in patients with Kt/V < 1.2 (P < 0.05). In patients with Kt/V ≥ 1.2, only IL-10 was positively and CXCL-10/IP-10 negatively correlated with creatinine levels (P < 0.05). Kt/V and creatinine levels exhibited variable predictive value (Kt/V = 27% to 37%, creatinine = 29% to 47%) to explain cytokines and chemokines circulating levels in patients with adequate and inadequate dialysis dose. Taken together, our findings provide evidence that in addition to modulating uremic toxins levels, such as urea and creatinine, dialysis dose is associated with circulating levels of inflammatory mediators. Thus, low Kt/V results and creatinine accumulation are potential indicators of the systemic inflammatory stress determined by up-regulation of proinflammatory cytokines and chemokines, and downregulation of anti-inflammatory cytokines.
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Quimiocina CXCL10/sangue , Creatinina/sangue , Inflamação/sangue , Interleucina-10/sangue , Falência Renal Crônica/terapia , Diálise Renal , Uremia/terapia , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Inflamação/diagnóstico , Falência Renal Crônica/sangue , Falência Renal Crônica/diagnóstico , Masculino , Pessoa de Meia-Idade , Diálise Renal/efeitos adversos , Resultado do Tratamento , Uremia/sangue , Uremia/diagnóstico , Adulto JovemRESUMO
BACKGROUND/AIMS: Chronic kidney disease is frequently accompanied by anemia, hypoxemia, and hypoxia. It has become clear that the impaired erythropoietin production and altered iron homeostasis are not the sole causes of renal anemia. Eryptosis is a process of red blood cells (RBC) death, like apoptosis of nucleated cells, characterized by Ca2+ influx and phosphatidylserine (PS) exposure to the outer RBC membrane leaflet. Eryptosis can be induced by uremic toxins and occurs before senescence, thus shortening RBC lifespan and aggravating renal anemia. We aimed to assess eryptosis and intracellular oxygen levels of RBC from hemodialysis patients (HD-RBC) and their response to hypoxia, uremia, and uremic toxins uptake inhibition. METHODS: Using flow cytometry, RBC from healthy individuals (CON-RBC) and HD-RBC were subjected to PS (Annexin-V), intracellular Ca2+ (Fluo-3/AM) and intracellular oxygen (Hypoxia Green) measurements, at baseline and after incubation with uremic serum and/or hypoxia (5% O2), with or without ketoprofen. Baseline levels of uremic toxins were quantified in serum and cytosol by high performance liquid chromatography. RESULTS: Here, we show that HD-RBC have less intracellular oxygen and that it is further decreased post-HD. Also, incubation in 5% O2 and uremia triggered eryptosis in vitro by exposing PS. Hypoxia itself increased the PS exposure in HD-RBC and CON-RBC, and the addition of uremic serum aggravated it. Furthermore, inhibition of the organic anion transporter 2 with ketoprofen reverted eryptosis and restored the levels of intracellular oxygen. Cytosolic levels of the uremic toxins pCS and IAA were decreased after dialysis. CONCLUSION: These findings suggest the participation of uremic toxins and hypoxia in the process of eryptosis and intracellular oxygenation.
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Eriptose , Eritrócitos/metabolismo , Oxigênio/sangue , Insuficiência Renal Crônica/sangue , Uremia/sangue , Adolescente , Adulto , Idoso , Anexina A5/sangue , Cálcio/sangue , Hipóxia Celular , Eritrócitos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/patologia , Uremia/patologiaRESUMO
Non-dialysable protein-bound uremic toxins (PBUTs) contribute to the development of cardiovascular disease (CVD) in chronic kidney disease (CKD) and vice versa. PBUTs have been shown to alter sphingolipid imbalance. Dihydroceramide desaturase 1 (Des1) is an important gatekeeper enzyme which controls the non-reversible conversion of sphingolipids, dihydroceramide, into ceramide. The present study assessed the effect of Des1 inhibition on PBUT-induced cardiac and renal effects in vitro, using a selective Des1 inhibitor (CIN038). Des1 inhibition attenuated hypertrophy in neonatal rat cardiac myocytes and collagen synthesis in neonatal rat cardiac fibroblasts and renal mesangial cells induced by the PBUTs, indoxyl sulfate and p-cresol sulfate. This is at least attributable to modulation of NF-κB signalling and reductions in ß-MHC, Collagen I and TNF-α gene expression. Lipidomic analyses revealed Des1 inhibition restored C16-dihydroceramide levels reduced by indoxyl sulfate. In conclusion, PBUTs play a critical role in mediating sphingolipid imbalance and inflammatory responses in heart and kidney cells, and these effects were attenuated by Des1 inhibition. Therefore, sphingolipid modifying agents may have therapeutic potential for the treatment of CVD and CKD and warrant further investigation.
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Doenças Cardiovasculares/induzido quimicamente , Oxirredutases/uso terapêutico , Esfingolipídeos/metabolismo , Toxinas Biológicas/efeitos adversos , Toxinas Biológicas/metabolismo , Uremia/sangue , Uremia/fisiopatologia , Animais , Inibidores Enzimáticos/uso terapêutico , Humanos , Modelos Animais , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/complicações , Esfingolipídeos/sangue , Toxinas Biológicas/sangueRESUMO
BACKGROUND AND OBJECTIVES: Residual native kidney function confers health benefits in patients on dialysis. It can facilitate control of extracellular volume and inorganic ion concentrations. Residual kidney function can also limit the accumulation of uremic solutes. This study assessed whether lower plasma concentrations of uremic solutes were associated with residual kidney function in pediatric patients on peritoneal dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Samples were analyzed from 29 pediatric patients on peritoneal dialysis, including 13 without residual kidney function and ten with residual kidney function. Metabolomic analysis by untargeted mass spectrometry compared plasma solute levels in patients with and without residual kidney function. Dialytic and residual clearances of selected solutes were also measured by assays using chemical standards. RESULTS: Metabolomic analysis showed that plasma levels of 256 uremic solutes in patients with residual kidney function averaged 64% (interquartile range, 51%-81%) of the values in patients without residual kidney function who had similar total Kt/Vurea. The plasma levels were significantly lower for 59 of the 256 solutes in the patients with residual kidney function and significantly higher for none. Assays using chemical standards showed that residual kidney function provides a higher portion of the total clearance for nonurea solutes than it does for urea. CONCLUSIONS: Concentrations of many uremic solutes are lower in patients on peritoneal dialysis with residual kidney function than in those without residual kidney function receiving similar treatment as assessed by Kt/Vurea.
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Nefropatias/terapia , Testes de Função Renal , Rim/fisiopatologia , Espectrometria de Massas , Metaboloma , Metabolômica , Diálise Peritoneal , Uremia/terapia , Adolescente , Fatores Etários , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Nefropatias/sangue , Nefropatias/diagnóstico , Nefropatias/fisiopatologia , Masculino , Diálise Peritoneal/efeitos adversos , Valor Preditivo dos Testes , Resultado do Tratamento , Estados Unidos , Uremia/sangue , Uremia/diagnóstico , Uremia/fisiopatologiaRESUMO
Cytokine storm is recognized as one of the factors contributing to organ failures and mortality in patients with COVID-19. Due to chronic inflammation, COVID-19 patients with diabetes mellitus (DM) or renal disease (RD) have more severe symptoms and higher mortality. However, the factors that contribute to severe outcomes of COVID-19 patients with DM and RD have received little attention. In an effort to investigate potential treatments for COVID-19, recent research has focused on the immunomodulation functions of mesenchymal stem cells (MSCs). In this study, the correlation between DM and RD and the severity of COVID-19 was examined by a combined approach with a meta-analysis and experimental research. The results of a systematic review and meta-analysis suggested that the odd of mortality in patients with both DM and RD was increased in comparison to those with a single comorbidity. In addition, in the experimental research, the data showed that high glucose and uremic toxins contributed to the induction of cytokine storm in human lung adenocarcinoma epithelial cells (Calu-3 cells) in response to SARS-CoV Peptide Pools. Of note, the incorporation of Wharton's jelly MSC-derived extracellular vesicles (WJ-EVs) into SARS-CoV peptide-induced Calu-3 resulted in a significant decrease in nuclear NF-κB p65 and the downregulation of the cytokine storm under high concentrations of glucose and uremic toxins. This clearly suggests the potential for WJ-EVs to reduce cytokine storm reactions in patients with both chronic inflammation diseases and viral infection.
Assuntos
Síndrome da Liberação de Citocina/prevenção & controle , Vesículas Extracelulares/fisiologia , Células-Tronco Mesenquimais/citologia , SARS-CoV-2/fisiologia , Geleia de Wharton/citologia , Adulto , Idoso , COVID-19/sangue , COVID-19/complicações , COVID-19/metabolismo , COVID-19/terapia , Células Cultivadas , Técnicas de Cocultura , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/virologia , Citocinas/genética , Citocinas/metabolismo , Complicações do Diabetes/sangue , Complicações do Diabetes/metabolismo , Complicações do Diabetes/terapia , Complicações do Diabetes/virologia , Diabetes Mellitus/sangue , Diabetes Mellitus/metabolismo , Diabetes Mellitus/terapia , Diabetes Mellitus/virologia , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Glucose/farmacologia , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/fisiologia , Gravidez , Toxinas Biológicas/metabolismo , Toxinas Biológicas/farmacologia , Cordão Umbilical/citologia , Uremia/sangue , Uremia/complicações , Uremia/metabolismo , Uremia/terapiaRESUMO
Uremic toxins are suggested to be involved in the pathophysiology of hemodialysis (HD) patients. However, the profile of uremic solutes in HD patients has not been fully elucidated. In this study using capillary electrophoresis mass spectrometry (CE-MS), we comprehensively quantified the serum concentrations of 122 ionic solutes before and after HD in 11 patients. In addition, we compared the results with those in non-HD patients with chronic kidney disease (CKD) to identify HD patient-specific solutes. We identified 38 solutes whose concentrations were higher in pre-HD than in CKD stage G5. Ten solutes among them did not significantly accumulate in non-HD CKD patients, suggesting that these solutes accumulate specifically in HD patients. We also identified 23 solutes whose concentrations were lower in both pre- and post-HD than in CKD stage G5. The serum levels of 14 solutes among them were not affected by renal function in non-HD patients, suggesting that these solutes tend to be lost specifically in HD patients. Our data demonstrate that HD patients have a markedly different profile of serum uremic solute levels compared to that in non-HD CKD patients. The solutes identified in our study may contribute to the pathophysiology of HD patients.
Assuntos
Eletroforese Capilar/métodos , Espectrometria de Massas/métodos , Diálise Renal/efeitos adversos , Uremia/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Metaboloma , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/embriologia , Insuficiência Renal Crônica/terapia , Uremia/etiologiaRESUMO
Optical monitoring of spent dialysate has been used to estimate the removal of water-soluble low molecular weight as well as protein-bound uremic toxins from the blood of end stage kidney disease (ESKD) patients. The aim of this work was to develop an optical method to estimate the removal of ß2-microglobulin (ß2M), a marker of middle molecule (MM) uremic toxins, during hemodialysis (HD) treatment. Ultraviolet (UV) and fluorescence spectra of dialysate samples were recorded from 88 dialysis sessions of 22 ESKD patients, receiving four different settings of dialysis treatments. Stepwise regression was used to obtain the best model for the assessment of ß2M concentration in the spent dialysate. The correlation coefficient 0.958 and an accuracy of 0.000 ± 0.304 mg/L was achieved between laboratory and optically estimated ß2M concentrations in spent dialysate for the entire cohort. Optically and laboratory estimated reduction ratio (RR) and total removed solute (TRS) of ß2M were not statistically different (p > 0.35). Dialytic elimination of MM uremic toxin ß2M can be followed optically during dialysis treatment of ESKD patients. The main contributors to the optical signal of the MM fraction in the spent dialysate were provisionally identified as tryptophan (Trp) in small peptides and proteins, and advanced glycation end-products.
Assuntos
Soluções para Hemodiálise/análise , Falência Renal Crônica/terapia , Diálise Renal , Toxinas Biológicas/sangue , Uremia/terapia , Microglobulina beta-2/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Produtos Finais de Glicação Avançada/sangue , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/diagnóstico , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Resultado do Tratamento , Triptofano/sangue , Uremia/sangue , Uremia/diagnósticoRESUMO
Accumulation of uremic toxins represents one of the major contributors to the rapid progression of chronic kidney disease (CKD), especially in patients with end-stage renal disease that are undergoing dialysis treatment. In particular, protein-bound uremic toxins (PBUTs) seem to have an important key pathophysiologic role in CKD, inducing various cardiovascular complications. The removal of uremic toxins from the blood with dialytic techniques represents a proved approach to limit the CKD-related complications. However, conventional dialysis mainly focuses on the removal of water-soluble compounds of low and middle molecular weight, whereas PBTUs are strongly protein-bound, thus not efficiently eliminated. Therefore, over the years, dialysis techniques have been adapted by improving membranes structures or using combined strategies to maximize PBTUs removal and eventually prevent CKD-related complications. Recent findings showed that adsorption-based extracorporeal techniques, in addition to conventional dialysis treatment, may effectively adsorb a significant amount of PBTUs during the course of the sessions. This review is focused on the analysis of the current state of the art for blood purification strategies in order to highlight their potentialities and limits and identify the most feasible solution to improve toxins removal effectiveness, exploring possible future strategies and applications, such as the study of a synergic approach by reducing PBTUs production and increasing their blood clearance.
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Diálise Renal , Insuficiência Renal Crônica/terapia , Toxinas Biológicas/sangue , Uremia/terapia , Adsorção , Animais , Humanos , Ligação Proteica , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Resultado do Tratamento , Uremia/sangue , Uremia/diagnósticoRESUMO
Imbalanced colonic microbial metabolism plays a pivotal role in generating protein-bound uraemic toxins (PBUTs), which accumulate with deteriorating kidney function and contribute to the uraemic burden of children with chronic kidney disease (CKD). Dietary choices impact the gut microbiome and metabolism. The aim of this study was to investigate the relation between dietary fibre and gut-derived PBUTs in paediatric CKD. Sixty-one (44 male) CKD children (9 ± 5 years) were prospectively followed for two years. Dietary fibre intake was evaluated by either 24-h recalls (73%) or 3-day food records (27%) at the same time of blood sampling for assessment of total and free serum levels of different PBUTs using liquid chromatography. We used linear mixed models to assess associations between fibre intake and PBUT levels. We found an inverse association between increase in fibre consumption (g/day) and serum concentrations of free indoxyl sulfate (-3.1% (-5.9%; -0.3%) (p = 0.035)), free p-cresyl sulfate (-2.5% (-4.7%; -0.3%) (p = 0.034)), total indole acetic acid (IAA) (-1.6% (-3.0%; -0.3%) (p = 0.020)), free IAA (-6.6% (-9.3%; -3.7%) (p < 0.001)), total serum p-cresyl glucuronide (pCG) (-3.0% (-5.6%; -0.5%) (p = 0.021)) and free pCG levels (-3.3% (-5.8%; -0.8%) (p = 0.010)). The observed associations between dietary fibre intake and the investigated PBUTs highlight potential benefits of fibre intake for the paediatric CKD population. The present observational findings should inform and guide adaptations of dietary prescriptions in children with CKD.
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Bactérias/metabolismo , Fibras na Dieta/administração & dosagem , Microbioma Gastrointestinal , Intestinos/microbiologia , Insuficiência Renal Crônica/dietoterapia , Toxinas Biológicas/sangue , Uremia/dietoterapia , Adolescente , Fatores Etários , Bélgica , Criança , Pré-Escolar , Disbiose , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Prognóstico , Estudos Prospectivos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/microbiologia , Uremia/sangue , Uremia/diagnóstico , Uremia/microbiologiaRESUMO
The retention of uremic toxins and their pathological effects occurs in the advanced phases of chronic kidney disease (CKD), mainly in stage 5, when the implementation of conventional thrice-weekly hemodialysis is the prevalent and life-saving treatment. However, the start of hemodialysis is associated with both an acceleration of the loss of residual kidney function (RKF) and the shift to an increased intake of proteins, which are precursors of uremic toxins. In this phase, hemodialysis treatment is the only way to remove toxins from the body, but it can be largely inefficient in the case of high molecular weight and/or protein-bound molecules. Instead, even very low levels of RKF are crucial for uremic toxins excretion, which in most cases are protein-derived waste products generated by the intestinal microbiota. Protection of RKF can be obtained even in patients with end-stage kidney disease (ESKD) by a gradual and soft shift to kidney replacement therapy (KRT), for example by combining a once-a-week hemodialysis program with a low or very low-protein diet on the extra-dialysis days. This approach could represent a tailored strategy aimed at limiting the retention of both inorganic and organic toxins. In this paper, we discuss the combination of upstream (i.e., reduced production) and downstream (i.e., increased removal) strategies to reduce the concentration of uremic toxins in patients with ESKD during the transition phase from pure conservative management to full hemodialysis treatment.
Assuntos
Dieta com Restrição de Proteínas , Falência Renal Crônica/terapia , Diálise Renal , Toxinas Biológicas/sangue , Uremia/terapia , Biomarcadores/sangue , Terapia Combinada , Dieta com Restrição de Proteínas/efeitos adversos , Progressão da Doença , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/fisiopatologia , Diálise Renal/efeitos adversos , Resultado do Tratamento , Uremia/sangue , Uremia/diagnóstico , Uremia/fisiopatologiaRESUMO
Red blood cells (RBCs) have been found to synthesize and release both nitric oxide (NO) and cyclic guanosine monophosphate (cGMP), contributing to systemic NO bioavailability. These RBC functions resulted impaired in chronic kidney disease (CKD). This study aimed to evaluate whether predialysis (conservative therapy, CT) and dialysis (peritoneal dialysis, PD; hemodialysis, HD) therapies used during CKD progression may differently affect NO-synthetic pathway in RBCs. Our data demonstrated that compared to PD, although endothelial-NO-synthase activation was similarly increased, HD and CT were associated to cGMP RBCs accumulation, caused by reduced activity of cGMP membrane transporter (MRP4). In parallel, plasma cGMP levels were increased by both CT and HD and they significantly decreased after hemodialysis, suggesting that this might be caused by reduced cGMP renal clearance. As conceivable, compared to healthy subjects, plasma nitrite levels were significantly reduced by HD and CT but not in patients on PD. Additionally, the increased carotid intima-media thickness (IMT) values did not reach the significance exclusively in patients on PD. Therefore, our results show that PD might better preserve the synthetic NO-pathway in CKD-erythrocytes. Whether this translates into a reduced development of uremic vascular complications requires further investigation.