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INTRODUCTION: Arteriovenous fistulas and grafts are lifelines for most hemodialysis patients, and a low access flow rate often requires patency-related intervention, such as angioplasty or thrombectomy, to prevent access failure. We examined whether early access flow rate, measured after initial fistula/graft cannulation, predicts vascular access patency-related intervention within 1 year. METHODS: This was a single-center retrospective cohort study. Among 172 patients undergoing surgical creation of a fistula/graft, 52 (30.2%) had documented access flow rates measurement by the Transonic™ ultrasound dilution technique, performed within an average of 48 days from initial access cannulation. The need for a patency-related intervention, defined as undergoing a fistulogram, angioplasty, thrombectomy, or surgical revision, was ascertained within 1 year. A receiver-operating characteristic curve (ROC) was generated to evaluate the diagnostic performance of first and average access flow rates for predicting patency-related intervention within 1 year. FINDINGS: Twenty-eight (53.8%) of the 52 study subjects required a patency-related intervention within 1 year. Their characteristics were not significantly different from those who did not require patency-related interventions. However, first access flow rates were significantly lower in patients requiring patency-related intervention compared to those who did not (898 vs. 1471 mL/min; p = 0.003), as were average access flow rates (841 vs. 1506 mL/min; p < 0.001). The ROC analyses revealed that first access flow rates and average access flow rates predicted the need for patency-related intervention within 1 year, with an area under-the-ROC curve of 0.743 (95% confidence interval [CI] 0.608, 0.877) and 0.775 (95% CI 0.648, 0.903), respectively, demonstrating acceptable discrimination. DISCUSSION: In adults undergoing hemodialysis, early access flow rate measurement can predict patency-related intervention within 1 year after initial vascular access cannulation. Additional studies are required to confirm these findings and identify optimal access flow rate cut-off values to predict vascular accesses at higher risk of stenosis.
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Diálise Renal , Grau de Desobstrução Vascular , Humanos , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Diálise Renal/métodos , Idoso , Derivação Arteriovenosa Cirúrgica/métodos , Estudos de CoortesRESUMO
Renal vein thrombosis (RVT), defined as the presence of a thrombus in the major renal vein or one of its tributaries, can present acutely or go unnoticed resulting in acute kidney injury or chronic kidney disease. RVT is associated with multiple etiologies, including nephrotic syndrome, thrombophilia, autoimmune disorders, and malignancy. Patients with systemic lupus erythematosus (SLE), a multiorgan autoimmune disorder, are predisposed to coagulopathy and thus are at a higher risk of venous and arterial thromboembolism. We describe the case of a 41-year-old man with SLE and biopsy-proven membranous glomerulonephritis (WHO class V lupus nephritis) in clinical remission with no evidence of nephrotic range proteinuria who presented with macroscopic hematuria and was diagnosed with acute-on-chronic bilateral RVT. We discuss the different causes of RVT and compare the clinical presentation, diagnostic imaging findings, and management of acute and chronic RVT.
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BACKGROUND: Acute kidney injury (AKI) is a well-recognized complication of coronavirus disease 2019 (COVID-19). The short and long-term outcomes of patients who develop AKI have not been well characterized. METHODS: In this multicenter retrospective cohort study, we describe the clinical characteristics and outcomes of critically ill adults with severe COVID-19 and AKI. Patient-level variables were extracted from the electronic medical record. Using nadir-to-peak serum creatinine, AKI was defined using the KDIGO definition. Multivariable logistic regression analyses examined factors associated with development of moderate-to-severe (stage 2-3) AKI, severe (stage-3) AKI, and the composite of renal replacement therapy (RRT) or in-hospital death. RESULTS: Among 459 critically ill adults with COVID-19, 371 (80.1%) developed AKI, with 179 (37.9%) developing stage-3 AKI. Male gender, black and Asian/Native American race, lower baseline estimated glomerular filtration rate (eGFR), higher body mass index (BMI), and higher Acute Physiology and Chronic Health Evaluation (APACHE) IV score were more prevalent among patients with severe AKI, as were systemic markers of inflammation. On multivariable analysis, male gender, black and Asian/Native American race, higher APACHE IV score, lower baseline eGFR, and higher BMI (mainly the highest BMI stratum ≥35 kg/m2) were independently associated with higher stages of AKI severity. Male gender, lower baseline eGFR, and higher APACHE IV score were also independently associated with the composite of RRT or in-hospital death. Moderate-to-severe AKI and severe AKI were independently associated with in-hospital death, and there was a significant interaction between BMI and moderate-to-severe AKI for the outcome of in-hospital death. Among 83 (18.1%) patients who required RRT, 27 (32.5%) survived, and 12 (44.4%) remained dialysis-dependent at discharge. At 3 and 6 months, 5 (41.7%) and 4 (33.3%) remained dialysis-dependent, respectively. CONCLUSIONS: AKI is common in critically ill adults with COVID-19. Several patient-level risk factors are associated with higher stages of AKI severity. BMI might be an effect modifier of AKI severity for in-hospital death. Among AKI survivors, there is a high rate of short- and long-term dialysis dependence.
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Injúria Renal Aguda , COVID-19 , Humanos , Masculino , COVID-19/complicações , Mortalidade Hospitalar , Estudos Retrospectivos , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapiaRESUMO
BACKGROUND: Continuous veno-venous hemofiltration (CVVH) and continuous veno-venous hemodialysis (CVVHD) are costly therapies reserved for use in critically ill patients with kidney failure. DESIGN: Quality improvement study at St. Elizabeth's Medical Center, Boston, MA, USA. SETTING AND PARTICIPANTS: Members of nephrology and pharmacy department, working alongside intensive care unit nursing staff and hospital administration, undertook an initiative to transition from CVVH to CVVHD, to simplify therapy administration, lessen need for electrolyte repletion, and reduce total treatment-related costs. QUALITY IMPROVEMENT PLAN: We postulated that conversion from CVVH to CVVHD would result in fewer filter clotting events, longer filter use (up to 72 hours), lower resource utilization, and confer overall cost benefit. Over 12 months, patients initiated on CVVH were identified. Following conversion to CVVHD, patients initiated on CVVHD over 9 months were identified. Patient characteristics, comorbidities, and hospital-related outcomes, as well as CRRT-related information including treatment modality, treatment duration, and treatment-related costs were obtained. MEASURES: Daily treatment-related costs, intensive care unit and hospital length of stay (LOS), and in-hospital mortality. RESULTS: During the baseline period, 77 patients were initiated on CVVH, and during the intervention period, 60 patients were initiated on CVVHD. Following conversion from CVVH to CVVHD, mean (±SD) daily total treatment cost decreased from $1813 ± $2143 to $775 ± $766 (P < 0.001). Conversion from CVVH to CVVHD had no impact on intensive care unit LOS (11.8 ± 9.7 vs. 12.4 ± 9.5 days; P = 0.53), hospital LOS (15.0 ± 11.1 vs. 16.4 ± 14.0 days; P = 0.89), or in-hospital mortality (58% vs. 60%; P = 0.85). LIMITATIONS: Nursing costs, costs of dialysis machine utilization, phosphate repletion, and systemic anti-coagulation were not studied. CONCLUSION: Transition from CVVH to CVVHD resulted in a significant cost benefit and reduced resource utilization. There was no difference in LOS and in-hospital mortality between the two treatment modalities.
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Injúria Renal Aguda , Terapia de Substituição Renal Contínua , Hemofiltração , Injúria Renal Aguda/terapia , Custos e Análise de Custo , Estado Terminal , Humanos , Diálise Renal , Terapia de Substituição RenalRESUMO
Malignancy-induced lactic acidosis (MILA), a rare paraneoplastic phenomenon, is mostly described with hematologic malignancies (lymphomas and leukemias) but has also been reported with solid tumors. It is a subset of type B lactic acidosis being mediated without evidence of tissue hypoperfusion. Lymphoma-induced lactic acidosis is often considered an oncologic emergency and is associated with an increased risk of mortality and poor prognosis. It has a complex pathophysiology centered in the "Warburg effect," i.e., the programming of cancer cells to depend on aerobic glycolysis for promotion of their proliferation and anabolic growth. The treatment of lymphoma-induced lactic acidosis is focused on prompt administration of chemotherapy. The role of alkali therapy in this setting is controversial and has limited proven benefit with a potential for worsening the lactic acidosis. If alkali therapy is used in the presence of severe acidemia to optimize cardiovascular status, it should be administered judiciously.
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Acidose Láctica/etiologia , Linfoma/complicações , Acidose Láctica/tratamento farmacológico , Idoso , Álcalis/uso terapêutico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Levofloxacin, a third-generation fluoroquinolone antibiotic, is rarely associated with neurotoxicity. Patients with advanced kidney disease are particularly vulnerable to this adverse effect. We present two elderly patients with kidney failure who developed levofloxacin-induced neurotoxicity, which was successfully treated with frequent hemodialysis, resulting in the full resolution of their symptoms. Neurotoxicity is a well-known side effect of fluoroquinolone antibiotics. Postulated mechanisms include inhibition of the gamma-aminobutyric acid A receptors and activation of the excitatory N-methyl-D-aspartate receptors. Risk factors include older age, kidney disease, pre-existing neurological disorders, and drug-drug interactions. While management of levofloxacin-induced neurotoxicity includes discontinuation of the drug and supportive care, hemodialysis is not recommended, despite available pharmacokinetic data in support of its dialyzability. The successful use of hemodialysis for the treatment of levofloxacin-induced neurotoxicity observed in our two patients with kidney failure should be further considered for rapid resolution of this rare fluoroquinolone-related adverse effect in patients with impaired kidney function.
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Antibacterianos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/complicações , Levofloxacino/efeitos adversos , Síndromes Neurotóxicas/terapia , Diálise Renal/métodos , Idoso de 80 Anos ou mais , Feminino , Humanos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Fatores de RiscoRESUMO
PURPOSE OF REVIEW: Sarcopenia and muscle weakness contribute to fragility and limit exercise tolerance among patients with CKD. This review focuses on the role of reduction in mitochondrial mass and function in the myopathy associated with CKD, causes for these muscle mitochondrial abnormalities, and potential therapeutic interventions that may improve mitochondrial biogenesis and function as well as skeletal muscle function and performance in patients with CKD. RECENT FINDINGS: Multiple abnormalities of mitochondrial structure, function, and composition have been shown in both experimental models and patients with CKD. A significant reduction in mitochondrial respiratory function and an increase in mitochondrial complex 1 enzyme activity has been demonstrated in the muscle tissue of male Sprague-Dawley rats following 5/6 nephrectomy. These changes were associated with a substantial reduction in skeletal muscle mitochondrial mass. In patients with CKD, in-vivo magnetic resonance and optical spectroscopy show significantly elevated resting skeletal muscle oxygen consumption and lower mean mitochondrial coupling ratio indicating disrupted muscle mitochondrial metabolism and uncoupling of oxidative phosphorylation. Skeletal muscle biopsies from patients with advanced CKD show lower mitochondrial volume density and mitochondrial DNA (mtDNA) copy number than controls. SUMMARY: Advanced CKD is associated with decreased exercise capacity, skeletal muscle weakness, and muscle atrophy. Impaired mitochondrial respiratory function, reduced muscle mitochondrial mass, and decreased energy production in skeletal muscle play a critical role in this 'acquired mitochondrial myopathy' of CKD. It is reasonable, therefore, to develop therapeutic interventions that enhance mitochondrial biogenesis and function as well as skeletal muscle function and performance in patients with CKD.
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DNA Mitocondrial/metabolismo , Mitocôndrias/patologia , Mitocôndrias/fisiologia , Miopatias Mitocondriais/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Animais , Fragilidade/etiologia , Humanos , Mitocôndrias/metabolismo , Miopatias Mitocondriais/etiologia , Músculo Esquelético/metabolismo , Consumo de Oxigênio , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Treinamento ResistidoRESUMO
BACKGROUND AND OBJECTIVES: CKD is a global public health problem with significant mortality and morbidity. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We examined the multivariable association of plasma levels of IL-1, IL-1 receptor antagonist, IL-6, TNF-α, TGF-ß, high-sensitivity C-reactive protein, fibrinogen, and serum albumin with progression of CKD in 3430 Chronic Renal Insufficiency Cohort study participants. RESULTS: Over a median follow-up time of 6.3 years, 899 participants reached the composite end point of ≥50% decline in eGFR from baseline or onset of ESRD. Elevated plasma levels of fibrinogen, IL-6, and TNF-α and lower serum albumin were associated with a greater decline in eGFR over time. After adjusting for demographics, BP, laboratory variables, medication use, and baseline eGFR, hazard ratios for the composite outcome were greater for the patients in the highest quartile of fibrinogen (hazard ratio, 2.05; 95% confidence interval, 1.64 to 2.55; P<0.001), IL-6 (hazard ratio, 1.44; 95% confidence interval, 1.17 to 1.77; P<0.01), and TNF-α (hazard ratio, 1.94; 95% confidence interval, 1.52 to 2.47; P<0.001) compared with those in the respective lowest quartiles. The hazard ratio was 3.48 (95% confidence interval, 2.88 to 4.21; P<0.001) for patients in the lowest serum albumin quartile relative to those in the highest quartile. When also adjusted for albuminuria, the associations of fibrinogen (hazard ratio, 1.49; 95% confidence interval, 1.20 to 1.86; P<0.001), serum albumin (hazard ratio, 1.52; 95% confidence interval, 1.24 to 1.87; P<0.001), and TNF-α (hazard ratio, 1.42; 95% confidence interval, 1.11 to 1.81; P<0.001) with outcome were attenuated but remained significant. CONCLUSIONS: Elevated plasma levels of fibrinogen and TNF-α and decreased serum albumin are associated with rapid loss of kidney function in patients with CKD.
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Proteína C-Reativa/metabolismo , Citocinas/sangue , Fibrinogênio/metabolismo , Inflamação/complicações , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Adulto , Idoso , Progressão da Doença , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Inflamação/sangue , Interleucina-1/sangue , Interleucina-6/sangue , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Albumina Sérica/metabolismo , Fator de Crescimento Transformador beta/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
The role of mitochondrial injury in the pathogenesis of complications of uremia is incompletely defined, although diminished bioenergetic capacity and the accumulation of mitochondrial DNA (mtDNA) mutations have been reported. This study was undertaken to evaluate the prevalence of mtDNA injury in 180 patients who had ESRD and were enrolled into the baseline phase of the HEMO study and to relate these markers to all-cause mortality. The mitochondrial injury markers studied in peripheral blood mononuclear cells were the mtDNA copy number per cell, measured by quantitative PCR, and the presence of the mtDNA(4977) mutation. After frequency-matching healthy control subjects for age, mtDNA copy number was lower among older dialysis patients compared with older healthy subjects (P = 0.01). A one-log increase in mtDNA copy number was independently associated with a decreased hazard for mortality (adjusted hazard ratio 0.64; 95% confidence interval 0.46 to 0.89). The mtDNA(4977) deletion was present in 48 (31%) patients and was independently associated with a decreased hazard for mortality (adjusted hazard ratio 0.33; 95% confidence interval 0.19 to 0.56). In summary, the mtDNA(4977) seems to predict survival in ESRD, but a reduced mitochondrial copy number seems to predict a poor outcome. Although further exploration of these associations is needed, evaluation of mitochondrial DNA copy number and somatic mtDNA mutations may provide simple genomic biomarkers to predict clinical outcomes among patients with ESRD.
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DNA Mitocondrial/genética , Diálise Renal/mortalidade , Adulto , Idoso , Feminino , Dosagem de Genes , Humanos , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
BACKGROUND: Adiponectin (ADPN) levels are consistently elevated among patients with advanced chronic kidney disease, but its relationship with cardiovascular outcomes in this population remains controversial. METHODS: We measured baseline and yearly plasma ADPN in 182 prevalent haemodialysis patients recruited to the Haemodialysis (HEMO) Study from two Boston centres. Plasma ADPN at baseline and during follow-up was studied in relation to prevalent cardiovascular disease (CVD) and cardiovascular and all-cause mortality. RESULTS: Baseline plasma ADPN levels were found to be approximately twofold higher than in the general population and correlated inversely with (log-transformed) CRP levels and (log-transformed) body mass index (BMI). Levels measured over time showed a gradual increase (0.95 microg/mL, 95% CI = 0.12-1.78 microg/mL; P = 0.03) by year, although this difference became non-significant after adjustment for covariates. Baseline ADPN levels were lower among patients with pre-existing CVD (adjusted OR of 0.67; P = 0.03). They also predicted all-cause mortality (P < 0.01) and the composite outcome of 'cardiovascular events/cardiovascular mortality' (P < 0.01); levels measured over time predicted the composite outcome of 'cardiovascular events and all-cause mortality' (P < 0.01). These relationships were non-linear (quadratic) with the hazard for each outcome increasing in the lower and upper ranges of the distribution of ADPN, and strengthened after adjustment for baseline covariates including serum albumin, CVD and the flux and dialysis dose categorization of the HEMO study. CONCLUSIONS: In summary, low plasma levels of ADPN were associated with inflammation and pre-existing CVD; ADPN levels predicted cardiovascular and mortality outcomes, the relationship being extensively confounded by multiple patient-related factors.
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Diálise Renal , Adiponectina/sangue , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Humanos , Interleucina-6/sangue , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/mortalidade , Estudos Prospectivos , Resultado do TratamentoRESUMO
A reversal in the association between traditional and nontraditional risk factors and clinical outcomes is often encountered in patients with chronic illness, including among those with advanced chronic kidney disease (CKD) on maintenance hemodialysis (MHD). The effects of the malnutrition-inflammation complex syndrome (MICS) may play a significant role in the reversal of this risk factor-outcomes association. the MICS, this syndrome complex is not universal in its prevalence among MHD patients. The significant inter- and intra-individual differences in the prevalence of inflammation, oxidative stress, and malnutrition, indicates the influence of genetic factors in this variability. In recent years, enormous advancement in the field of molecular genetics, genomics and bioinformatics, have revolutionized studies of the genetic epidemiology of several diseases. However, genetic association studies are at a preliminary stage in the population with advanced CKD (Table 1). Preliminary studies of the impact of polyphisms in inflammation and oxidative stress-related genes and genes affecting body composition and metabolism suggest that genetic variation may indeed affect the phenotype of the MHD population. Further, some of these gene polymorphisms may also contribute to a reversal of the association between traditional risk factors, such as BMI, blood pressure, and cholesterol and clinical outcomes in this vulnerable patient population. Genetic studies in patients with advanced CKD pose enormous challenges, including recruitment of sufficient numbers of patients to achieve adequate statistical power, resolution of immense genotypic and phenotypic heterogeneity, and gene-environment and gene-gene interactions. However, well-designed adequately powered studies with carefully defined phenotypes may potentially allow definition of risk profiles characterized by combinations of relevant Single nucleotide polymorphisms in the setting of given environmental factors. Accurate risk stratification that takes into account genetic information would allow more informed targeting of pharmacologic intervention and better refined clinical trial methodologies.
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Falência Renal Crônica/genética , Falência Renal Crônica/terapia , Diálise Renal , Composição Corporal/genética , Proteína C-Reativa/genética , Citocinas/genética , Fatores Epidemiológicos , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-10/genética , Interleucina-6/genética , Canais Iônicos/genética , Falência Renal Crônica/complicações , Proteínas Mitocondriais/genética , Estresse Oxidativo/genética , Receptores Ativados por Proliferador de Peroxissomo/genética , Polimorfismo Genético , Receptores de Glucocorticoides/genética , Fatores de Risco , Fator de Crescimento Transformador beta1/genética , Fator de Necrose Tumoral alfa/genética , Proteína Desacopladora 1RESUMO
In an in vivo crossover trial, we compared a cellulosic with a synthetic dialyzer with respect to polymorphonuclear cells (PMN) function and apoptosis, cytokine serum levels and synthesis by peripheral blood mononuclear cells (PBMC), and complement activation. Twenty hemodialysis (HD) patients were assigned in alternate order to HD with cellulose acetate (CA) or polysulfone (PS) dialyzer. After 2 weeks, patients were crossed over to the second dialyzer and treated for another 2 weeks. Apoptosis was assessed by flow cytometry in freshly isolated PMN. Phagocytosis and production of peroxide by PMN were studied by flow cytometry in whole blood. PBMC were isolated from blood samples and incubated for 24 h with or without lipopolysaccharide (LPS). There was no impact of dialyzer biocompatibility on PMN apoptosis and function, cytokine synthesis by PBMC or on their serum levels, serum levels of C3a, and terminal complement complex (TCC). Nevertheless, after HD, serum levels of complement correlated negatively with PMN phagocytosis and peroxide production, and positively with PMN apoptosis and cytokine production by PBMC. Although the results did not show a dialyzer advantage on the immunologic parameters, complement activation may have modulated cell function and apoptosis after HD.
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Apoptose/efeitos dos fármacos , Materiais Biocompatíveis/farmacologia , Celulose/análogos & derivados , Membranas Artificiais , Neutrófilos/efeitos dos fármacos , Polímeros/farmacologia , Sulfonas/farmacologia , Adolescente , Adulto , Idoso , Celulose/farmacologia , Citocinas/biossíntese , Humanos , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Diálise Renal/instrumentaçãoRESUMO
The role of urinary biomarkers of kidney injury in the prediction of adverse clinical outcomes in acute renal failure (ARF) has not been well described. The relationship between urinary N-acetyl-beta-(D)-glucosaminidase activity (NAG) and kidney injury molecule-1 (KIM-1) level and adverse clinical outcomes was evaluated prospectively in a cohort of 201 hospitalized patients with ARF. NAG was measured by spectrophotometry, and KIM-1 was measured by a microsphere-based Luminex technology. Mean Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score was 16, 43% had sepsis, 39% required dialysis, and hospital mortality was 24%. Urinary NAG and KIM-1 increased in tandem with APACHE II and Multiple Organ Failure scores. Compared with patients in the lowest quartile of NAG, the second, third, and fourth quartile groups had 3.0-fold (95% confidence interval [CI] 1.3 to 7.2), 3.7-fold (95% CI 1.6 to 8.8), and 9.1-fold (95% CI 3.7 to 22.7) higher odds, respectively, for dialysis requirement or hospital death (P < 0.001). This association persisted after adjustment for APACHE II, Multiple Organ Failure score, or the combined covariates cirrhosis, sepsis, oliguria, and mechanical ventilation. Compared with patients in the lowest quartile of KIM-1, the second, third, and fourth quartile groups had 1.4-fold (95% CI 0.6 to 3.0), 1.4-fold (95% CI 0.6 to 3.0), and 3.2-fold (95% CI 1.4 to 7.4) higher odds, respectively, for dialysis requirement or hospital death (P = 0.034). NAG or KIM-1 in combination with the covariates cirrhosis, sepsis, oliguria, and mechanical ventilation yielded an area under the receiver operator characteristic curve of 0.78 (95% CI 0.71 to 0.84) in predicting the composite outcome. Urinary markers of kidney injury such as NAG and KIM-1 can predict adverse clinical outcomes in patients with ARF.
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Acetilglucosaminidase/urina , Injúria Renal Aguda/urina , Glicoproteínas de Membrana/urina , Insuficiência de Múltiplos Órgãos/etiologia , Sepse/etiologia , APACHE , Injúria Renal Aguda/complicações , Idoso , Área Sob a Curva , Biomarcadores/urina , Feminino , Receptor Celular 1 do Vírus da Hepatite A , Mortalidade Hospitalar , Humanos , Cirrose Hepática/etiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Oligúria/etiologia , Prognóstico , Estudos Prospectivos , Receptores Virais , Diálise Renal/estatística & dados numéricos , Respiração Artificial/estatística & dados numéricosRESUMO
Reactive oxygen species are important mediators of injury in acute renal failure (ARF). Although polymorphisms that affect key pro- and antioxidant enzymes might alter the susceptibility to oxidative stress-mediated injury, the use of genetic epidemiology for the study of oxidative stress-related genes has received little attention in ARF. The relationship of single-nucleotide polymorphisms in the coding region (C to T substitution at position +242) of the pro-oxidant enzyme NADPH oxidase p22phox subunit gene and in the promoter region (C to T substitution at position -262) of the antioxidant enzyme catalase gene to adverse clinical outcomes was evaluated prospectively in a cohort of 200 hospitalized patients with established ARF of mixed cause and severity. Genomic DNA was extracted from peripheral blood leukocytes and analyzed with a restriction fragment length polymorphism PCR method. Genotype-phenotype associations were characterized by measuring circulating nitrotyrosine and catalase activity. Observed and expected genotype frequencies were not significantly different, and overall baseline characteristics were not significantly different according to the various genotype groups. A genotype-phenotype association was demonstrable between the NADPH oxidase p22phox genotypes and plasma nitrotyrosine level (P = 0.06), as well as between the catalase genotypes and whole-blood catalase activity (P < 0.001). Compared with the NADPH oxidase p22phox CC genotype group, the T-allele group had a higher cumulative probability of remaining hospitalized (P = 0.03). Compared with the NADPH oxidase p22phox CC genotype, the T-allele carrier state was associated with 2.1-fold higher odds for dialysis requirement or hospital death (P = 0.01). This association persisted with 2.0- to 2.2-fold higher odds for this composite outcome after adjustment for race; gender; age; and the Acute Physiology and Chronic Health Evaluation II score (P = 0.03), the Multiple Organ Failure score (P = 0.01), or presence of sepsis (P = 0.02). The polymorphism in the gene that encodes the NADPH oxidase p22phox subunit at position +242 is associated with dialysis requirement or hospital death among patients with ARF. Larger studies are needed to confirm these relationships.
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Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Catalase/genética , NADPH Oxidases/genética , Injúria Renal Aguda/terapia , Idoso , Sequência de Bases , Biomarcadores/sangue , Estudos de Coortes , Primers do DNA/genética , Feminino , Variação Genética , Genótipo , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Polimorfismo de Nucleotídeo Único , Prognóstico , Regiões Promotoras Genéticas , Estudos Prospectivos , Terapia de Substituição Renal , Tirosina/análogos & derivados , Tirosina/sangueRESUMO
The 350,000 maintenance hemodialysis (MHD) patients in the United States have an unacceptably high mortality rate of >20%/year. Almost half of all deaths are assumed to be cardiovascular. Markers of kidney disease wasting (KDW) such as hypoalbuminemia, anorexia, body weight and fat loss, rather than traditional cardiovascular risk factors, appear to be the strongest predictors of early death in these patients. The KDW is closely related to oxidative stress (SOX). Such SOX markers as serum myeloperoxidase are associated with pro-inflammatory cytokines and poor survival in MHD patients. Identifying the conditions that modulate the KDW/SOX-axis may be the key to improving outcomes in MHD patients. Dysfunctional lipoproteins such as a higher ratio of the high-density lipoprotein inflammatory index (HII) may engender or aggravate the KDW, whereas functionally intact or larger lipoprotein pools, as in hypercholesterolemia and obesity, may mitigate the KDW in MHD patients. Hence, a reverse epidemiology or "bad-gone-good" phenomenon may be observed. Diet and gene and their complex interaction may lead to higher proportions of pro-inflammatory or oxidative lipoproteins such as HII, resulting in the aggravation of the SOX and inflammatory processes, endothelial dysfunction, and subsequent atherosclerotic cardiovascular disease and death in MHD patients. Understanding the factors that modulate the KDW/SOX complex and their associations with genetic polymorphism, nutrition, and outcomes in MHD patients may lead to developing more effective strategies to improve outcomes in this and the 20 to 30 million Americans with chronic disease states such as individuals with chronic heart failure, advanced age, malignancies, AIDS, or cachexia.
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Dieta , Inflamação/etiologia , Falência Renal Crônica/terapia , Estresse Oxidativo , Diálise Renal/efeitos adversos , Doenças Cardiovasculares/etiologia , Citocinas/genética , Humanos , Falência Renal Crônica/complicações , Lipoproteínas/metabolismo , Modelos Biológicos , Polimorfismo Genético , Prognóstico , Fatores de RiscoRESUMO
BACKGROUND: Oxidative stress is prevalent in dialysis patients and has been implicated in the pathogenesis of cardiovascular disease and anaemia. We conducted a systematic review and meta-analysis to examine the effect of Excebrane, a vitamin E-coated cellulose-based dialyser, on circulating biomarkers of lipid peroxidation, as surrogate markers of oxidative stress. METHODS: The primary sources used to identify candidate studies included PubMed, the Cochrane Central Register of Controlled Trials, a bibliography provided by the dialyser manufacturer, and a manual search of abstracts from proceedings of scientific meetings and review articles. Studies were selected for analysis if their design included a comparator group (primarily within patient comparison, i.e. pre- and post-study evaluations). For the meta-analysis, we computed the overall change of the outcome from baseline using a random-effects model. A supplemental analysis was performed in which the absolute levels of these biomarkers of lipid peroxidation were converted to a common unit by calculating standardized effect sizes. RESULTS: Fourteen peer-reviewed articles met the criteria. The studies consisted of 11 single arm, one randomized crossover and two randomized controlled trials, with a total of 37 to 158 evaluable patients, according to the outcome of interest analysed. Due to the paucity of randomized trials, the meta-analysis was limited to the Excebrane arm of each study. When the studies were combined according to similar measurement units, the overall mean decrease in malondialdehyde (MDA) level was -0.3 mM (95% CI, -0.5 to -0.1 mM; seven studies) and -0.8 nmol/mg low-density lipoprotein (LDL) (95% CI, -1.3 to -0.4 nmol/mg LDL; three studies), respectively. The summary estimate revealed a non-significant decrease in pre-dialysis thiobarbituric acid reactive substances (TBARS) level of 0.4 microM (95% CI, -1.2 to 0.4 microM; three studies). When the MDA and TBARS studies were combined using the standardized effect size, the mean decrease in these biomarkers of lipid peroxidation was statistically significant at -1.7 units (95% CI, -2.7, -0.7 units; 13 studies). A meta-analysis on the effect of Excebrane on pre-dialysis levels of oxidized-LDL could not be performed due to study heterogeneity. CONCLUSION: The conversion of dialysis patients to a vitamin E-coated dialyser is associated with an improvement in circulating biomarkers of lipid peroxidation, which is of potential clinical benefit.
Assuntos
Biomarcadores/análise , Peroxidação de Lipídeos , Diálise Renal/instrumentação , Antioxidantes/química , Antioxidantes/farmacologia , Ensaios Clínicos Controlados como Assunto , Humanos , Malondialdeído/análise , PubMed , Diálise Renal/métodos , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Vitamina E/química , Vitamina E/farmacologiaRESUMO
The anemia of chronic kidney disease is associated with cardiovascular disease, decreased quality of life, and mortality. The introduction of recombinant human erythropoietin (rHuEPO) has transformed the management of this condition. However, a significant proportion of patients fail to respond to even high doses of rHuEPO. Several factors have been implicated in the hyporesponsiveness to rHuEPO. Iron deficiency, whether absolute or functional, is considered the most important, and maintenance of adequate iron stores reduces rHuEPO requirements among patients on hemodialysis. However, traditional indices of iron that are currently utilized may not reflect iron stores accurately, and there is also increasing concern regarding the potential long-term toxicity of parenteral iron therapy. Infection and inflammation also influence the response to rHuEPO, both by disruption of iron metabolism and by eliciting the release of cytokines that inhibit erythropoiesis. Oxidative stress may contribute to rHuEPO hyporesponsiveness directly by promoting lipid peroxidation in cell membranes, leading to increased erythrocyte fragility and reduced life span and also through its strong association with inflammation. Severe hyperparathyroidism can lead to a reduced number of erythroid progenitor cells. Inadequate dialysis dose, aluminum overload, nutritional factors such as deficiencies of carnitine, vitamin B12, folic acid, and vitamin C can also reduce the efficacy of rHuEPO therapy. Hyporesponsiveness to rHuEPO presents a challenge to both diagnosis and management in an era where optimizing response to rHuEPO is critical both in limiting the burgeoning costs of anemia management and improving clinical outcomes in the dialysis population.
Assuntos
Anemia/tratamento farmacológico , Eritropoetina/uso terapêutico , Alumínio/sangue , Anemia/etiologia , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Deficiência de Vitaminas/complicações , Carnitina/deficiência , Humanos , Hiperparatireoidismo/complicações , Inflamação/complicações , Falência Renal Crônica/terapia , Estresse Oxidativo , Proteínas Recombinantes , Diálise Renal/efeitos adversosRESUMO
With the current understanding that atherosclerosis is an inflammatory disorder, markers of the associated systemic inflammatory response have been extensively studied as predictors of cardiovascular disease. Recently the use of high-sensitivity C-reactive protein (hsCRP) has been proposed for risk assessment in individuals at intermediate risk of coronary heart disease. The traditional view of inflammatory biomarkers, including CRP, regards them as risk markers rather than risk factors. Either category of marker would serve a diagnostic role, monitor disease activity, and indicate the efficacy of therapy or changing prognosis. However a risk factor with a causal role would be a potential target for therapy. This review discusses the available evidence that argues for and against a causal role for inflammatory biomarkers, with specific reference to CRP, in the atherosclerotic process.
Assuntos
Proteína C-Reativa/análise , Doenças Cardiovasculares/sangue , Falência Renal Crônica/sangue , Biomarcadores/sangue , Citocinas/análise , Humanos , Diálise Renal , Medição de RiscoRESUMO
Cardiovascular disease (CVD) is the most important cause of morbidity and mortality in dialysis patients. The high prevalence of CVD is due to the cumulative effects of multiple risk factors from the early stages of chronic kidney disease (CKD). Familial predispositions to CVD, CKD, and their respective risk factors are well known, and it is likely that genetic factors determine the interindividual variability in risks for disease. Advances in genomic technology have facilitated the study of genetic variation--most commonly single nucleotide polymorphisms (SNPs) in candidate genes--and their associations with disease. This review examines CVD in dialysis patients as a model of a complex disease, discusses the approach to gene polymorphism association studies, including the roles of gene-environment and gene-gene interactions and provides an overview of available studies.
Assuntos
Doenças Cardiovasculares/genética , Falência Renal Crônica/genética , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Humanos , Fenótipo , Diálise Renal , Fatores de RiscoRESUMO
BACKGROUND: Interleukin-6 (IL-6) is a mediator and marker of the chronic inflammatory process that is responsible for much of the morbidity and mortality seen in hemodialysis (HD) patients. This study evaluated circulating plasma IL-6 as a predictor of all-cause mortality and cardiovascular mortality and studied its relationship to prevalent comorbidity and hypoalbuminemia, in a cohort of stable HD patients enrolled in the HEMO study. METHODS: Clinical data included demographic, medical, and routine laboratory parameters. Comorbidities were graded using the Index of Co-Existing Diseases (ICED). Outcomes of interest were all-cause mortality and cardiovascular mortality. Blood samples were drawn at enrollment and annually, and plasma IL-6 levels measured with high-sensitivity enzyme-linked immunosorbent assay. RESULTS: Median plasma IL-6 level in 206 patients was 7.9 pg/mL (range, 0.1 to 90.3 pg/mL) and was higher in patients with vascular disease ( P = 0.03), higher ICED scores ( P = 0.01), and lower Karnofsky indices ( P < 0.01). Serum albumin was inversely related to plasma IL-6 levels ( P = 0.03, r = -0.16). Unadjusted median survival time was 1,209 days in the lowest quartile of plasma IL-6 and 806 days in the highest ( P = 0.02, log rank test). A 1-log increase in plasma IL-6 was associated with a 1.19-fold higher adjusted risk for all-cause mortality ( P = 0.04; 95% confidence interval, 1.01 to 1.40) and a 1.43-fold higher adjusted risk of cardiovascular mortality ( P = 0.02; 95% confidence interval, 1.06 to 1.92). Hazard ratio estimates were higher when IL-6 levels over time were incorporated as a time-dependent covariate. CONCLUSION: Plasma IL-6 levels are strongly associated with comorbidity in HD patients and are a powerful predictor of cardiovascular and all-cause mortality.