RESUMO
BACKGROUND: We analysed 5-year treatment with agalsidase alfa enzyme replacement therapy in patients with Fabry's disease who were enrolled in the Fabry Outcome Survey observational database (FOS). METHODS: Baseline and 5-year data were available for up to 181 adults (126 men) in FOS. Serial data for cardiac mass and function, renal function, pain, and quality of life were assessed. Safety and sensitivity analyses were done in patients with baseline and at least one relevant follow-up measurement during the 5 years (n=555 and n=475, respectively). FINDINGS: In patients with baseline cardiac hypertrophy, treatment resulted in a sustained reduction in left ventricular mass (LVM) index after 5 years (from 71.4 [SD 22.5] g/m(2.7) to 64.1 [18.7] g/m(2.7), p=0.0111) and a significant increase in midwall fractional shortening (MFS) from 14.3% (2.3) to 16.0% (3.8) after 3 years (p=0.02). In patients without baseline hypertrophy, LVM index and MFS remained stable. Mean yearly fall in estimated glomerular filtration rate versus baseline after 5 years of enzyme replacement therapy was -3.17 mL/min per 1.73 m(2) for men and -0.89 mL/min per 1.73 m(2) for women. Average pain, measured by Brief Pain Inventory score, improved significantly, from 3.7 (2.3) at baseline to 2.5 (2.4) after 5 years (p=0.0023). Quality of life, measured by deviation scores from normal EuroQol values, improved significantly, from -0.24 (0.3) at baseline to -0.17 (0.3) after 5 years (p=0.0483). Findings were confirmed by sensitivity analysis. No unexpected safety concerns were identified. INTERPRETATION: By comparison with historical natural history data for patients with Fabry's disease who were not treated with enzyme replacement therapy, long-term treatment with agalsidase alfa leads to substantial and sustained clinical benefits. FUNDING: Shire Human Genetic Therapies AB.
Assuntos
Doença de Fabry/tratamento farmacológico , alfa-Galactosidase/uso terapêutico , Adulto , Doença de Fabry/fisiopatologia , Feminino , Testes de Função Cardíaca , Humanos , Isoenzimas/uso terapêutico , Testes de Função Renal , Masculino , Medição da Dor , Qualidade de Vida , Proteínas Recombinantes , Sistema de Registros , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Mycophenolic acid (MPA) is a selective inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme of de novo synthesis of guanine nucleotides. The isoenzyme IMPDH2 predominates in activated lymphocytes, and its inhibition by MPA is part of standard immunosuppressive regimens. Yet, there are significant unexplained differences in efficacy and tolerability among patients. The objective of this study was to analyze whether frequent variants in the IMPDH2 gene lead to changes in IMPDH activity and to differences in responsiveness to MPA therapy. All 14 exons and intron-exon boundary regions of IMPDH2 were sequenced from genomic DNA probes from 100 healthy individuals. Two novel exonic single-nucleotide polymorphisms were identified in 1% and one intronic polymorphism (rs11706052) in 19% of the study population. Lymphocyte IMPDH activity and proliferation under three MPA concentrations (2.5, 10 and 25 micromol l(-1)) were compared in rs11706052 carriers and wild-type individuals. The presence of rs11706052 polymorphism reduced the antiproliferative effect of MPA on lymphocytes by approximately 50% compared with the IMPDH2 wild-type form at therapeutic relevant concentrations of 10 micromol l(-1) and 25 micromol l(-1). We conclude that a poorer response to MPA therapy can be explained in some individuals by the presence of the rs11706052 polymorphism.
Assuntos
IMP Desidrogenase/genética , Imunossupressores/antagonistas & inibidores , Ácido Micofenólico/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Humanos , Imunossupressores/uso terapêutico , Linfócitos/efeitos dos fármacos , Linfócitos/enzimologia , Ácido Micofenólico/uso terapêutico , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Fabry disease is a rare X-linked lysosomal storage disorder characterised by severe multisystemic involvement that leads to major organ failure and premature death in affected men and women. Over the past 7 years, the Fabry Outcome Survey (FOS) has collected data on the natural history of Fabry disease, and the long-term efficacy and safety of enzyme-replacement therapy. This paper provides an update on the first analysis of FOS data. DESIGN: Baseline data on clinical manifestations and causes of death in a cohort of 1453 patients (699 male, 754 female) from 19 countries worldwide were analysed. Causes of death of affected relatives were analysed separately. RESULTS: The most frequently reported signs and symptoms of Fabry disease were neurological. Cardiac, ocular, gastrointestinal, dermatological, auditory and renal manifestations were also common. The principal causes of death among 181 affected relatives of patients in FOS (most of whom had died before 2001) were renal failure in males (42%) and cerebrovascular disease in females (25%). In contrast, of the 42 patients enrolled in FOS whose deaths were reported between 2001 and 2007, cardiac disease was the main cause of death in both male (34%) and female (57%) patients. CONCLUSION: These data suggest that the importance of renal disease as a cause of death in patients with Fabry disease is decreasing while the importance of cardiac disease is increasing. This pattern probably reflects improvements in the management of renal disease in patients with Fabry disease.
Assuntos
Doença de Fabry/mortalidade , Doença de Fabry/patologia , Adulto , Causas de Morte , Distribuição de Qui-Quadrado , Criança , Estudos de Coortes , Coleta de Dados , Feminino , Humanos , Nefropatias/mortalidade , Masculino , Fatores SexuaisRESUMO
AIMS: Elevated calcitonin concentrations in dialysis patients had led to thyroidectomy for a benign C-cell hyperplasia in dozens of patients in the past decade. The prevalence of hypercalcitoninemia, however, has not been examined in a large cohort of dialysis patients. METHODS: We, therefore, measured calcitonin concentrations in 283 dialysis patients. We used different reference intervals: according to the threshold to perform further stimulation tests (i.e. > 10 pg/ml) and new reference intervals for the currently used assay (i.e. serum calcitonin concentration < 11.5 pg/ml in men and < 4.6 pg/ml in women). RESULTS: Median calcitonin concentrations of men and women were 12 (1; 290) pg/ml vs 2 pg/ml (1; 45), respectively, (p < 0.0001). The prevalence of hypercalcitoninemia was 10% in women and 58% in men using a cut-off of 10 pg/ml. Applying the new reference intervals 31% of women and 54% of men presented with hypercalcitoninemia. All patients with basal calcitonin concentrations above 50 pg/ml were men (highest calcitonin concentration was 290 pg/ml). Two of them underwent thyroidectomy and had C-cell hyperplasia. CONCLUSION: The prevalence of hypercalcitoninemia in dialysis patients amounts to 46%. It is more common in male than in female dialysis patients.
Assuntos
Biomarcadores Tumorais/sangue , Calcitonina/sangue , Carcinoma Medular/epidemiologia , Falência Renal Crônica/terapia , Transplante de Rim , Diálise Renal/métodos , Neoplasias da Glândula Tireoide/epidemiologia , Áustria/epidemiologia , Carcinoma Medular/sangue , Carcinoma Medular/etiologia , Feminino , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Medições Luminescentes , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/etiologia , TireoidectomiaRESUMO
OBJECTIVE: Dialysis-related amyloidosis (DRA) is a severe complication of maintenance hemodialysis (HD). Given the predominant deposition of beta(2)-microglobulin (beta2m) fibrils on articular cartilage in early DRA, we investigated the significance of beta2m and its relationship to distinct cartilage biomarkers in early DRA diagnosis in HD patients. Furthermore, we assessed the effects of beta2m on articular chondrocytes in vitro. METHODS: Serum samples from 133 patients were collected before and after HD. Type II collagen cleavage product (C2C), procollagen II c-propeptide (CPII), aggrecan chondroitin sulfate 846 epitope (CS-486) and cartilage oligomeric matrix protein (COMP) levels were determined by enzyme-linked immunosorbent assay. Primary bovine articular chondrocytes were cultured as monolayers and incubated with beta2m at 1.5mg/l and 20mg/l. Cartilage glucosaminoglycan synthesis was measured by [(35)S]sulfate incorporation. mRNA expression of interleukin (IL)-1beta, matrix metalloproteinases (MMPs)-3 and -9 was measured by reverse-transcriptase polymerase chain reaction (RT-PCR). RESULTS: Incubation with beta2m at 20mg/l significantly decreased matrix biosynthesis. PCR analysis revealed an increase of IL-1beta, as well as MMPs-3 and -9 on the mRNA level. C2C/CPII, CS-486 and COMP levels were increased only in a subset of patients without a significant correlation with beta2m concentrations. A subgroup analysis elucidated an increase in type II collagen degradation during the first years of HD, as shown by the elevation of C2C/CPII ratio. CONCLUSION: beta2m exerted anti-anabolic effects on articular chondrocytes in vitro and might be involved in cartilage degradation in HD patients. beta2m serum levels, however, did not reflect cartilage degradation in DRA. The assessment of C2C/CPII, CS-486 or COMP concentrations apparently has minor relevance in DRA diagnosis in HD patients. However, the increased type II collagen breakdown within 5 years after HD onset possibly mirrors the early stages of DRA. Thus, the C2C/CPII ratio could be employed in longitudinal studies, since it may reflect a risk for DRA related arthropathy development in a subset of patients.
Assuntos
Amiloidose/etiologia , Cartilagem Articular/metabolismo , Colágeno Tipo II/metabolismo , Diálise Renal/efeitos adversos , Microglobulina beta-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/sangue , Animais , Biomarcadores/metabolismo , Doenças das Cartilagens , Estudos de Casos e Controles , Bovinos , Células Cultivadas , Condrócitos/metabolismo , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Serum creatinine concentration alone as a marker of kidney function is inadequate. Thus several equations for estimating glomerular filtration rate (eGFR) have been proposed within the last years. PATIENTS AND METHODS: In our study we compared three frequently used equations, the abbreviated modification of diet in renal disease (MDRD) formula, the extended MDRD formula and the recently proposed Mayo clinic equation in a large patient cohort. RESULTS: A total of 244 507 patients attending the Vienna General Hospital were evaluated for their kidney function and three equations for eGFR were compared. The median age of the patients was 51 years (ranging from 18.0 to 102.6 years) with 44.3% males (n = 108 527). We observed a significant increase of patients with eGFR classes four and five (according to Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines) with advanced age. Whereas approximately 1% of patients < 30 years presented with eGFR classes four and five (defined as eGFR < 30 mL min(-1) 1.73 m(-2)), this prevalence increased up to approximately 12% in patients at the age of 80 years or older. All three equations showed comparable results for eGFR classes four and five. The proportion of patients with mild to moderate impairment of kidney function is higher using both MDRD equations. CONCLUSIONS: The MDRD equations (particularly the abbreviated MDRD formula) result in considerably higher rates of eGFR classes two and three compared to the Mayo Clinic equation, while all three were comparable in classes four and five. This should be considered when eGFR is used in the diagnosis of chronic kidney disease.
Assuntos
Taxa de Filtração Glomerular/fisiologia , Falência Renal Crônica/classificação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
AIMS: Anemia is commonly observed among patients with chronic kidney disease (CKD). No such information is available for patients with a history of systemic vasculitis. METHODS: We examined the prevalence of anemia, the response to therapy with erythropoiesis-stimulating agents (ESA), and the association of anemia with the kidney function in clinically stable patients with Wegener's granulomatosis in a retrospective, single-center study. RESULTS: The mean hemoglobin concentration of 36 patients (mean age: 58 years; 15 female, 21 male; mean duration of disease: 4.6 years) was 13.0+/-2.1 g/dl, and the mean estimated glomerular filtration rate (eGFR) was 41+/-21 ml/min/1.73 m(2). 14 of 36 patients (38.8%) presented with anemia (hemoglobin concentration < 12 g/dl in women, < 13 g/dl in men, or ESA therapy). In patients with a CKD Stage 3 or 4, anemia was present about twice as much as compared to the Third National Health and Nutrition Examination Survey (NHANES III) population. The hemoglobin concentration, however, was not associated with a change of kidney function (p = 0.1578). CONCLUSIONS: We found a higher prevalence of anemia in patients with Wegener's granulomatosis, as compared to the NHANES III population. The hemoglobin concentrations showed no association with changes of kidney function.
Assuntos
Anemia/epidemiologia , Granulomatose com Poliangiite/complicações , Anemia/tratamento farmacológico , Anemia/etiologia , Creatinina/sangue , Darbepoetina alfa , Quimioterapia Combinada , Eritropoetina/análogos & derivados , Eritropoetina/uso terapêutico , Feminino , Taxa de Filtração Glomerular/fisiologia , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/fisiopatologia , Hematínicos/uso terapêutico , Hemoglobinas/metabolismo , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Prevalência , Prognóstico , Proteínas Recombinantes , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programs have been initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx-markers into routine care, because the evidence base is currently limited to specific, individual drug-gene pairs. The Ubiquitous Pharmacogenomics (U-PGx) Consortium, which has been funded by the European Commission's Horizon-2020 program, aims to address this unmet need. In a prospective, block-randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions [PREPARE]), pre-emptive genotyping of a panel of clinically relevant PGx-markers, for which guidelines are available, will be implemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost-effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi-ethnic, and multihealthcare system approach.
Assuntos
Testes Farmacogenômicos/métodos , Testes Farmacogenômicos/estatística & dados numéricos , Projetos de Pesquisa , Biomarcadores , Análise Custo-Benefício , Registros Eletrônicos de Saúde/organização & administração , Europa (Continente) , Genótipo , Humanos , Testes Farmacogenômicos/economia , Testes Farmacogenômicos/tendências , Guias de Prática Clínica como Assunto , Medicina de Precisão/métodos , Estudos Prospectivos , Resultado do TratamentoRESUMO
Hemodialysis patients develop metabolic acidosis due to their impaired excretion of daily produced protons (H+). The following report will show a rare case of severe metabolic alkalosis (predialysis pH 7.52, base excess (BE) +17) in a hemodialysis woman caused by self-provoked upper gastrointestinal H+ losses based on an eating disorder. Treatment with a proton pump inhibitor resulted in the normalization of acid/base homeostasis (predialysis pH 7.40, BE +1.6).
Assuntos
2-Piridinilmetilsulfinilbenzimidazóis/uso terapêutico , Alcalose/tratamento farmacológico , Alcalose/etiologia , Antiulcerosos/uso terapêutico , Transtornos da Alimentação e da Ingestão de Alimentos/complicações , Doenças Renais Císticas/terapia , Diálise Renal/efeitos adversos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Pessoa de Meia-Idade , PantoprazolRESUMO
AIM: Fabry disease is a rare lysosomal storage disorder caused by deficient activity of alpha-galactosidase A, resulting in progressive cellular accumulation of glycolipids, which may ultimately result in endstage renal disease. We examined the effects of enzyme replacement therapy (ERT) with Agalsidase-alpha on renal function using data from a large international database, the Fabry Outcome Survey (FOS). METHODS: This analysis was based on 1,040 serum creatinine measurements in 201 patients with Fabry disease, aged 20 - 60 years, with serum creatinine concentrations of less than 2 mg/dl and duration of ERT of up to 4.7 years. Both pretreatment and treatment data were used to examine independent predictors of changes in serum creatinine. In a second approach longitudinal serum creatinine measurements from 1 year before treatment, at baseline and 1 and 2 years after the start of treatment were analyzed in 20 patients with chronic kidney disease (CKD) Stage 2 and 3. RESULTS: We found an independent negative association between serum creatinine and time on Agalsidase-alpha treatment (p < 0.05). Renal function declined significantly (p < 0.05) in the year before treatment. After 1 year of treatment, however, the decline in estimated glomerular filtration rate had been halted, and renal function was preserved for up to 2 years. CONCLUSIONS: In conclusion, ERT with Agalsidase-alpha is associated with decrease of serum creatinine and may prevent the deterioration of renal function in patients with Fabry disease.
Assuntos
Doença de Fabry/tratamento farmacológico , Doença de Fabry/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , alfa-Galactosidase/uso terapêutico , Adulto , Idoso , Estudos de Coortes , Creatinina/sangue , Doença de Fabry/complicações , Feminino , Humanos , Isoenzimas/uso terapêutico , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/etiologia , Falência Renal Crônica/fisiopatologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise MultivariadaRESUMO
Thrombotic microangiopathy (TMA) is a clinical syndrome that is characterized by hemolysis, thrombocytopenia, and acute kidney injury, known as atypical hemolytic syndrome (aHUS), thrombotic thrombocytopenic purpura (TTP), and shigatoxin-associated HUS (STEC-HUS) among others. Several diseases, like malignoma, infections, malignant hypertension, or autoimmune disease can result in secondary TMAs. aHUS is caused by a hyperactivated complement system. Identification of the underlying causes of the TMA is the most important issue and directly associated with treatment success. In case of secondary TMAs, treatment of the actual disease is the most important step, while in case of complement-mediated HUS treatment of choice is plasma exchange or anticomplement agents. For the treatment of TTP, rapid initiation of plasma exchange or plasma infusion is the treatment of choice. Patients with STEC-HUS should solely receive supportive treatment.
Assuntos
Unidades de Terapia Intensiva , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/etiologia , Adulto , Biópsia , Ativação do Complemento/fisiologia , Diagnóstico Diferencial , Feminino , Síndrome Hemolítico-Urêmica/sangue , Síndrome Hemolítico-Urêmica/diagnóstico , Síndrome Hemolítico-Urêmica/etiologia , Síndrome Hemolítico-Urêmica/terapia , Humanos , Rim/patologia , Plasmaferese , Transtornos Puerperais/sangue , Transtornos Puerperais/diagnóstico , Transtornos Puerperais/etiologia , Transtornos Puerperais/terapia , Púrpura Trombocitopênica Trombótica/sangue , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/etiologia , Púrpura Trombocitopênica Trombótica/terapia , Microangiopatias Trombóticas/sangue , Microangiopatias Trombóticas/terapiaRESUMO
UNLABELLED: Appropriate measurement of the glomerular filtration rate (GFR) is important for the assessment of renal function. This paper reviews the methods used to assess GFR in clinical trials of enzyme replacement therapy (ERT) in patients with Fabry disease, which include inulin clearance, 24-hour creatinine clearance, chromium ethylene diamine tetraacetate (51Cr-EDTA) clearance and cystatin C concentrations. GFR has also been estimated using calculations based on creatinine clearance (the Cockcroft-Gault formula) and the Modification of Diet in Renal Disease (MDRD) equation. Analysis of the results of these studies shows that there are striking discrepancies between estimated and measured GFR. For example, the MDRD equation overestimates GFR in patients with Fabry disease who have normal renal function. In addition, cystatin C has been shown to be of limited use for measuring renal function during ERT, because it is influenced by other factors such as age, gender and weight. CONCLUSION: The use of exact methods, such as inulin clearance, 124I-iothalamate, 99mTc-DTPA, 51Cr-EDTA and iohexol, appears to be mandatory for a robust evaluation of the effects of ERT on GFR in patients with Fabry disease.
Assuntos
Doença de Fabry/complicações , Taxa de Filtração Glomerular/fisiologia , Nefropatias/sangue , Nefropatias/complicações , Adulto , Creatinina/sangue , Cistatina C , Cistatinas/sangue , Ácido Edético/sangue , Monitoramento Ambiental , Doença de Fabry/tratamento farmacológico , Comportamento Alimentar , Feminino , Humanos , Inulina/sangue , Nefropatias/fisiopatologia , Testes de Função Renal , Masculino , Taxa de Depuração Metabólica/fisiologia , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos , Fatores de Risco , Pentetato de Tecnécio Tc 99m , alfa-Galactosidase/uso terapêuticoRESUMO
We describe the validation of a cytochemical method to detect a cytolytic cell-specific lymphoid serine protease which can be upregulated during viral infection and allogeneic stimulation. The cytolytic cell specificity was ascertained by demonstrating a high correlation between BLT substrate-specific serine protease (SP) activity and cytotoxicity of in vivo and in vitro stimulated lymphocytes. The presence of SP in peripheral blood lymphocytes was compared with their capacity to kill K562 targets in a lectin-dependent cytotoxicity assay. The correlation coefficient was 0.92 and 0.93 at E:T ratios 10:1 and 20:1 respectively. In allogeneic mixed lymphocyte cultures an increase of SP activity in effector lymphocytes was paralleled by an augmentation of cytotoxic capacity towards stimulator target cells. SP+ granules showed intracellular polarization to the effector/target cell interface during conjugate formation. These results together with previous studies suggest that this method provides a sensitive assay which predicts the cytolytic potential present in a lymphocyte population.
Assuntos
Serina Endopeptidases/metabolismo , Linfócitos T Citotóxicos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Grânulos Citoplasmáticos/enzimologia , Citotoxicidade Imunológica , Granzimas , Histocitoquímica , Humanos , Técnicas In Vitro , Teste de Cultura Mista de Linfócitos , Coloração e RotulagemRESUMO
The formation of prostacyclin (PGI2) and thromboxane A2 and the release of beta-thromboglobulin (beta-TG) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the microvasculature made to determine bleeding time, was studied in patients with end-stage chronic renal failure undergoing regular haemodialysis and in normal subjects. In the uraemic patients, levels of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were 1.3-fold to 6.3-fold higher than the corresponding values in the control subjects indicating an increased PGI2 formation in chronic uraemia. Formation of thromboxane B2 (TxB2) at the site of plug formation in vivo and during whole blood clotting in vitro was similar in the uraemic subjects and in the normals excluding a major defect in platelet prostaglandin metabolism in chronic renal failure. Significantly smaller amounts of beta-TG were found in blood obtained from the site of vascular injury as well as after in vitro blood clotting in patients with chronic renal failure indicating an impairment of the alpha-granule release in chronic uraemia. We therefore conclude that the haemorrhagic diathesis commonly seen in patients with chronic renal failure is--at least partially--due to an acquired defect of the platelet alpha-granule release and an increased generation of PGI2 in the microvasculature.
Assuntos
Plaquetas/metabolismo , Vasos Sanguíneos/metabolismo , Epoprostenol/biossíntese , Falência Renal Crônica/metabolismo , 6-Cetoprostaglandina F1 alfa/biossíntese , Adolescente , Adulto , Idoso , Tempo de Sangramento , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal , Tromboxano A2/biossíntese , Tromboxano B2/biossíntese , beta-Tromboglobulina/biossínteseRESUMO
Cardiac diseases account for almost 50% of deaths in long-term dialysis patients. Left ventricular dysfunction is present in approximately 80% of these patients and is highly predictive of future ischemic heart disease, cardiac failure, and death. Anemia has been identified as one of several risk factors responsible for cardiac complications. Cardiovascular consequences of renal anemia begin relatively early in the course of renal failure and progress with the decline of renal function and also during dialysis therapy. In chronic renal failure patients with severe anemia (hemoglobin levels <10 g/dL), increased cardiac output, high left ventricular mass, left ventricular end-diastolic and end-systolic diameters, and cardiac symptoms improve after partial correction of anemia (hemoglobin levels >11 g/dL according to the European Best Practice Guidelines). It is disappointing that normalization of hemoglobin levels has only minor effects with respect to regression of left ventricular hypertrophy and left ventricular dilation. There is no benefit of hemoglobin normalization on all-cause mortality of dialysis patients or on survival of end-stage renal disease patients with congestive heart failure or ischemic heart disease. Therefore, prevention of renal anemia may be more efficient than its treatment. Hypertension is one of the major side effects of recombinant human erythropoietin (rHuEPO) therapy. Multiple factors are involved in rHuEPO-induced hypertension. High blood pressure can usually be controlled readily in the majority of the patients.
Assuntos
Anemia/tratamento farmacológico , Anemia/epidemiologia , Doenças Cardiovasculares/epidemiologia , Eritropoetina/uso terapêutico , Falência Renal Crônica/epidemiologia , Comorbidade , Eritropoetina/efeitos adversos , Hematócrito , Humanos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Incidência , Falência Renal Crônica/terapia , Proteínas Recombinantes , Diálise RenalRESUMO
In a randomized crossover trial, we compared a simple citrate anticoagulation protocol for high-flux hemodialysis with standard anticoagulation by low-molecular-weight heparin (dalteparin). Primary end points were urea reduction rate (URR), Kt/V, and control of electrolyte and acid-base homeostasis. Secondary end points were bleeding time at vascular puncture sites and markers of activation of platelets, coagulation, and fibrinolysis. Solute removal during citrate dialysis was excellent (URR, 0.71 +/- 0.06; Kt/V, 1.55 +/- 0.3) and similar to results of conventional bicarbonate hemodialysis anticoagulation with dalteparin (URR, 0.72 +/- 0.04; Kt/V, 1.56 +/- 0.2). Electrolyte control was effective with both anticoagulation regimens, and total and ionized calcium, sodium, potassium, and phosphate concentrations at the end of dialysis did not differ. Alkalemia was less frequent after citrate than conventional dialysis (pH 7.5 in 25% versus 62% of patients; mean pH at end of dialysis, 7.46 +/- 0.06 versus 7.51 +/- 0.07; P < 0.01). Bleeding time at puncture sites was shorter by 30% after citrate compared with dalteparin anticoagulation (5.43 +/- 2.80 versus 7.86 +/- 2.93 minutes; P < 0.001). Activation of platelets, coagulation, and fibrinolysis was modest for both treatments and occurred mainly within the dialyzer during dalteparin treatment and in the vascular-access region during citrate anticoagulation. Citrate-related adverse events were not observed. We conclude that citrate anticoagulation for high-flux hemodialysis is feasible and safe using a simple infusion protocol.
Assuntos
Anticoagulantes/uso terapêutico , Citratos/uso terapêutico , Dalteparina/uso terapêutico , Diálise Renal , Adulto , Idoso , Análise de Variância , Bicarbonatos/sangue , Cálcio/sangue , Cloretos/sangue , Estudos Cross-Over , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/efeitos dos fármacos , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Magnésio/sangue , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/efeitos dos fármacos , Fosfatos/sangue , Fator Plaquetário 4/efeitos dos fármacos , Fator Plaquetário 4/metabolismo , Potássio/sangue , Protrombina/efeitos dos fármacos , Diálise Renal/métodos , Sódio/sangueRESUMO
The effect of the combined 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T and 1298A-->C genotype on total homocysteine (tHcy), folate, and vitamin B(12) plasma levels was investigated in 983 subjects, including 415 hemodialysis patients, 179 peritoneal dialysis patients, and 389 healthy individuals. Mean tHcy plasma concentrations were 27.2 +/- 15.8 micromol/L in hemodialysis patients, 25.4 +/- 19.1 micromol/L in peritoneal dialysis patients, and 8.9 +/- 3.5 micromol/L in healthy individuals. Hyperhomocysteinemia (tHcy > 15 micromol/L) was detected in 81.6% of patients and 2.6% of controls. Multiple stepwise regression analysis showed that the MTHFR 677C-->T/1298A-->C genotype (CC/AA, CC/AC, CC/CC, CT/AA, CT/AC, TT/AA), vitamin use, age, folate and vitamin B(12) plasma level were significant predictors of tHcy plasma levels. Analysis of variance showed that this effect of MTHFR genotypes on tHcy level was caused by significantly greater tHcy levels in 677TT/1298AA hemodialysis and peritoneal dialysis patients versus other genotypes. Compound heterozygous controls (677CT/1298AC genotype) had significantly greater tHcy levels compared with 677CC/1298AA controls. There was no major effect of MTHFR polymorphisms on folate and vitamin B(12) plasma concentrations. This study shows that the MTHFR 677TT/1298AA genotype, but not the 677CT/1298AC genotype, is a significant predictor of tHcy plasma levels in dialysis patients.
Assuntos
Diálise , Homocisteína/sangue , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Adulto , Idoso , Feminino , Ácido Fólico/sangue , Frequência do Gene , Genótipo , Humanos , Falência Renal Crônica/terapia , Modelos Lineares , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2) , Pessoa de Meia-Idade , Diálise Peritoneal , Polimorfismo Genético , Diálise Renal , Vitamina B 12/sangueRESUMO
The prevalence of the methionine synthase (MTR) 2756A-->G polymorphism among individuals with severely elevated total homocysteine (tHcy) plasma levels is unknown. Therefore, 1,716 subjects, including 415 hemodialysis patients, 179 peritoneal dialysis patients, 733 kidney graft recipients, and 389 healthy subjects, were investigated. The distribution of MTR 2756A-->G, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T/1298A-->C, genotypes among study participants with extremely high tHcy plasma levels (>90th percentile) was compared with the genotype distribution of subjects with very low tHcy plasma levels (<10th percentile). The prevalence of MTR 2756AG and GG genotypes alone did not differ between individuals with extremely high or extremely low tHcy levels (P = 0.7402; odds ratio [OR], 1.076; 95% confidence interval [CI], 0.697 to 1.662). Conversely, combined MTR and MTHFR genotypes (MTR 2756AG and 2756GG and MTHFR 677TT/1298AA and 677CT/1298AC) were found more often in the highest (n = 34) compared with the lowest plasma tHcy decile (n = 19; P = 0.0252; OR, 1.983; 95% CI, 1.079 to 3.643). The number of patients with the wild-type MTR and MTHFR genotype was three times greater in the lowest compared with the highest decile (17 versus 6 patients, respectively; P = 0.0155; OR, 0.330; 95% CI, 0.126 to 0.861). In summary, our study shows that the 2756A-->G transition of MTR in combination with MTHFR 677TT/1298AA and 677CT/1298AC can be associated with extremely high tHcy plasma levels.
Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Homocisteína/sangue , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Adulto , Idoso , DNA/genética , Feminino , Ácido Fólico/sangue , Frequência do Gene , Genótipo , Humanos , Nefropatias/sangue , Nefropatias/terapia , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2) , Pessoa de Meia-Idade , Diálise Peritoneal , Mutação Puntual , Polimorfismo de Fragmento de Restrição , Diálise Renal , Vitamina B 12/sangueRESUMO
Extracorporeal detoxification has been proposed to treat patients with hepatic encephalopathy (HE) not responding to standard therapy. To investigate the biocompatibility of a cuprophane charcoal-based detoxification device, a prospective, randomized, controlled study was performed. Of 41 consecutive patients with cirrhosis and HE grade II or III who did not improve with conventional treatment, 20 patients (median age, 56 years; range, 33 to 71 years; 13 men) were randomly assigned to either ongoing conventional treatment or one additional 6-hour treatment with a sorbent suspension dialysis system. Main outcome parameters were physiological function and blood parameters of biocompatibility. In the 10 patients undergoing combined conventional and sorbent suspension dialysis treatment, blood pressure remained unchanged and body temperature and heart rate increased (P: < 0.01). Platelet count decreased (medians, from 75 to 26 g/L; P: < 0.001) and international normalized ratio increased after combined treatment (2.0 to 2.2; P: < 0.001). Three patients developed bleeding complications during treatment or shortly after. Treated patients showed increases in levels of plasma elastase (104 to 586 microg/L; P: = 0.001), tumor necrosis factor-alpha (5.4 to 7.5 pg/mL; P: = 0.04), and interleukin-6 (118 to 139 pg/mL; P: = 0.04), but not interferon-gamma and E-selectin. No changes were observed in the 10 patients treated conventionally. In conclusion, despite technical refinements compared with charcoal hemoperfusion, biocompatibility of sorbent suspension dialysis is still very limited. Clinical complications were apparently caused by blood-membrane interactions and disseminated intravascular coagulation. We suggest further developments in design and appropriate strategies of anticoagulation to improve the biocompatibility of artificial liver support.
Assuntos
Celulose/análogos & derivados , Carvão Vegetal , Encefalopatia Hepática/terapia , Cirrose Hepática/complicações , Adulto , Idoso , Materiais Biocompatíveis , Feminino , Encefalopatia Hepática/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal/instrumentação , Diálise Renal/métodos , Desintoxicação por Sorção/instrumentação , Desintoxicação por Sorção/métodosRESUMO
The effectiveness of intravenous folinic acid or intravenous folic acid for the treatment of hyperhomocysteinemia of hemodialysis patients is unknown. In a randomized, controlled, double-blind trial, 66 hemodialysis patients were administered either 15 mg of folic acid or an equimolar amount (16.1 mg) of folinic acid intravenously three times weekly. Normalization of total homocysteine (tHcy) plasma levels after 4 weeks of treatment was achieved in 10 patients (30.3%) in the folic-acid group and 6 patients (18.2%; P: = 0.389) in the folinic-acid group (normalization at any time during the study period in 39.4% and 33.3% of the patients; P: = 0.798). The relative reduction in tHcy plasma levels at week 4 was 32.2% in the folic-acid group and 34.1% in the folinic-acid group. A high baseline tHcy plasma concentration (P: = 0.00001), methylenetetrahydrofolate reductase (MTHFR) 677TT/1298AA genotype (P: = 0.03540), and low red blood cell folate concentrations (P: = 0.02285) were associated with a better relative response to treatment. Normalization of tHcy plasma levels was dependent on a lower baseline tHcy level (P: = 0.01976), younger age (P: = 0.00896), and MTHFR 677TT/1298AA or 677CT/1298AC genotypes (P: = 0.00208 and P: = 0.02320, respectively). A 4-week course of intravenous folinic acid is not superior to intravenous folic acid in reducing elevated tHcy plasma levels in hemodialysis patients. The response to treatment is predicted by tHcy plasma level, red blood cell folate content, and MTHFR genotype.