RESUMEN
AIMS: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. METHODS AND RESULTS: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. CONCLUSION: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.
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Aterosclerosis , Infarto del Miocardio , Oxazolidinonas , Adulto , Aterosclerosis/tratamiento farmacológico , Atorvastatina/uso terapéutico , Método Doble Ciego , Humanos , Infarto del Miocardio/tratamiento farmacológico , Oxazolidinonas/efectos adversos , Resultado del TratamientoRESUMEN
Chronic kidney disease (CKD) is accompanied by coronary artery disease (CAD) in most patients. In this article we describe differences in the pathogenesis, diagnosis, and treatment of CAD compared with patients without kidney impairment. The histological phenotype as well as the clinical presentation of acute and chronic coronary syndromes differ from those of patients with normal kidney function. The risk of cardiovascular events including death is strikingly increased with higher stages of CKD. Traditional but even more nontraditional cardiovascular risk factors are contributing to this increase. Screening and diagnostic procedures show limited sensitivity and specificity. Lifestyle modification is important for reducing the progression of both CKD and CAD. A special emphasis should be placed on physical exercising. Equally important is a strict antihypertensive therapy due to the very high incidences of hypertension in CKD patients. Blockade of the renin-angiotensin-system is imperative providing that adverse effects can be managed. Target blood pressure should be at 130â¯mmâ¯Hg systolic. Antiglycemic treatment should be implemented with metformin and SGLT2-inhibitors as first-line therapy, and glomerular filtration rate thresholds must be respected for both drugs. The risk of hypoglycemia is increased with worsening kidney function. Statins are indicated for up to stage 5 CKD. When a revascularization procedure is indicated (percutaneous intervention or bypass grafting), higher rates or peri-interventional morbidity and mortality must be anticipated. Taken together, the available literature on patients with CKD and CAD is clearly restricted compared with that on CAD patients with preserved kidney function. Mechanisms of arteriosclerosis and atheromatosis in CKD deserve more attention in the future. One major innovation in the field is SGLT2-inhibitor treatment with its concordant advantages for kidney and cardiac protection.
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Enfermedad de la Arteria Coronaria , Hipertensión , Fallo Renal Crónico , Intervención Coronaria Percutánea , Insuficiencia Renal Crónica , Tasa de Filtración Glomerular , Humanos , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/terapiaRESUMEN
BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage and multi-system disorder due to mutations in the α-galactosidase A (α-GalA) gene. We investigated the impact of individual amino acid exchanges in the α-GalA 3D-structure on the clinical phenotype of FD patients. PATIENTS AND METHODS: We enrolled 80 adult FD patients with α-GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the α-GalA 3D-structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD-specific treatment. RESULTS: Patients with active site or buried mutations showed a severe phenotype with multi-organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. α-GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso-Gb3 levels were higher (P < 0.01 in men; <0.05 in women). CONCLUSIONS: The type of amino acid exchange location in the α-GalA 3D-structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.
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Enfermedad de Fabry/genética , alfa-Galactosidasa/genética , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/enzimología , Humanos , Conformación Molecular , Mutación MissenseRESUMEN
The treatment of chronic but stable coronary artery disease is based on the stages of chronic kidney disease (CKD) stages G1-2 and stages G3-G5, distinguishing between advanced kidney disease (stages G3-G5) and end-stage kidney disease (G5D) treated by dialysis. In Germany, national guidelines are followed for patients with normal kidney function in addition to the recommendations of Kidney Disease - Improving Global Outcomes (KDIGO) for CKD patients. These guidelines focus on standard of care and include treatment with aspirin, statins, beta-blockers, inhibitors of the renin-angiotensin system, and sodium glucose cotransporters for patients with cardiovascular disease. Revascularization strategies follow a more pragmatic approach for the fragile, comorbid, and aging patient population. Younger patients appear to benefit from surgical interventions. Treatment of acute events is currently administered independent of the patient's kidney function, but there is no consensus yet on the best strategy. The focus of our efforts should be, via more controlled studies, to avoid "navigating through the darkness" to reach the end of the tunnel.
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Antagonistas Adrenérgicos beta/uso terapéutico , Antagonistas de Receptores de Angiotensina/uso terapéutico , Aspirina/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Insuficiencia Renal Crónica/complicaciones , Alemania , HumanosRESUMEN
BACKGROUND: The X-linked Fabry disease (FD) is a multiorgan disorder due to alpha-galactosidase A (α-GAL) deficiency with consequent lysosomal accumulation of globotriaosylceramide (Gb3). We established the immunocytochemical detection of Gb3 in blood cells of FD patients as a new method for FD diagnostics, follow-up and treatment control. METHODS: We enrolled 67 FD patients (37 men, 30 women) and 52 healthy controls (26 men, 26 women). PBMC were isolated from whole venous blood and 3x105 cells were immunoreacted with antibodies against CD77 as a marker for Gb3. Using fluorescence microscopy, the mean percentage of Gb3 positive PBMC was determined by an investigator blinded to subject allocation. As a second method, we qualitatively assessed Gb3 positive cells in blood smears. RESULTS: Gb3 deposits were unequivocally visible in PBMC and in blood smears. Men (P < 0.001) and women (P < 0.01) with classical FD had more Gb3-positive PBMC than healthy controls, whose samples only occasionally showed positive cells. The number of Gb3 positive PBMC was negatively correlated with α-GAL activity and positively correlated with plasma lyso-Gb3 levels. Only the PBMC Gb3 load but not plasma lyso-Gb3 reflected short- and long-term effects of enzyme replacement therapy (P < 0.01). CONCLUSIONS: Gb3 can be visualized in PBMC and blood smears and can be used as a novel marker for diagnostics, follow-up and treatment control in FD.
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Antígenos de Carbohidratos Asociados a Tumores/sangre , Enfermedad de Fabry/sangre , Leucocitos Mononucleares/metabolismo , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Análisis Mutacional de ADN , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/diagnóstico , Enfermedad de Fabry/genética , Enfermedad de Fabry/terapia , Femenino , Estudios de Seguimiento , Tamización de Portadores Genéticos , Genotipo , Humanos , Lisosomas/metabolismo , Masculino , Microscopía Fluorescente , Persona de Mediana Edad , Factores Sexuales , Adulto JovenRESUMEN
BACKGROUND: Inhibitory antibodies towards enzyme replacement therapy (ERT) are associated with disease progression and poor outcome in affected male patients with lysosomal disorders such as Fabry disease (FD). However, little is known about the impact of immunosuppressive therapy on ERT inhibition in these patients with FD. METHODS: In this retrospective study, we investigated the effect of long-term immunosuppression on ERT inhibition in male patients with FD (n = 26) receiving immunosuppressive therapy due to kidney (n = 24) or heart (n = 2) transplantation. RESULTS: No ERT-naïve transplanted patient (n = 8) developed antibodies within follow-up (80 ±72 months) after ERT initiation. Seven (26.9%) patients were tested ERT inhibition positive prior to transplantation. No de novo ERT inhibition was observed after transplantation (n = 18). In patients treated with high dosages of immunosuppressive medication such as prednisolone, tacrolimus and mycophenolate-mofetil/mycophenolate acid, ERT inhibition decreased after transplantation (n = 12; P = 0.0160). Tapering of immunosuppression (especially prednisolone) seemed to re-increase ERT inhibition (n = 4, median [range]: 16.6 [6.9; 36.9] %; P = 0.0972) over time. One ERT inhibition-positive patient required interventions with steroid therapy and increased doses of tacrolimus, which also lowered ERT inhibition. CONCLUSION: We conclude that the immunosuppressive maintenance therapy after transplantations seems to be sufficient to prevent de novo ERT inhibition in ERT-naïve patients. Intensified high dosages of immunosuppressive drugs are associated with decreased antibody titres and decreased ERT inhibition in affected patients, but did not result in long-term protection. Future studies are needed to establish ERT inhibition-specific immunosuppressive protocols with long-term modulating properties to warrant an improved disease course in ERT inhibition-positive males.
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Anticuerpos Neutralizantes/efectos de los fármacos , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/inmunología , Trasplante de Corazón , Inmunosupresores/efectos adversos , Trasplante de Riñón , Adolescente , Adulto , Anticuerpos Neutralizantes/sangre , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
Ocular manifestation of sarcoidosis occurs in up to 60% of patients with confirmed systemic sarcoidosis and represents one of the most common forms of noninfectious uveitis. In known pulmonary sarcoidosis, ocular involvement can occur in up to 80% of cases. Sarcoidosis can also present only in the eye, without a systemic manifestation (ocular sarcoidosis). Typically, ocular sarcoidosis shows bilateral granulomatous uveitis and can involve all parts of the eye. Apart from an acute anterior uveitis, chronic intermediate or posterior uveitis can be found. In order to prevent a severe reduction of visual acuity leading to blindness, early diagnosis and treatment is essential. For diagnosis, specific clinical signs involving the eye (bilateral granulomatous changes in all parts of the eye) and typical laboratory investigations (angiotensin-converting enzyme, ACE; lysozyme; soluble interleukin 2 receptor, sIL2R; chest Xray; chest CT) have to be taken into account, since biopsy to prove noncaseating granulomas is not performed with changes restricted to the eye due to the high risk of vision loss. Ocular sarcoidosis mostly responds well to local or systemic steroid treatment. If the therapeutic effect is insufficient, immunosuppressive agents and biologics can be applied.
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Corticoesteroides/administración & dosificación , Antiinflamatorios/administración & dosificación , Sarcoidosis/diagnóstico , Sarcoidosis/terapia , Uveítis/diagnóstico , Uveítis/terapia , Diagnóstico Diferencial , Medicina Basada en la Evidencia , Humanos , Resultado del TratamientoRESUMEN
BACKGROUND: Fabry disease is characterized by a progressive deposition of sphingolipids in different organ systems, whereby cardiac involvement leads to death. We hypothesize that lysosomal storage of sphingolipids in the heart as occurring in Fabry disease does not reflect in higher cardiac lipid concentrations detectable by 1H magnetic resonance spectroscopy (MRS) at 3 Tesla. METHODS: Myocardial lipid content was quantified in vivo by 1H-MRS in 30 patients (12 male, 18 female; 18 patients treated with enzyme replacement therapy) with genetically proven Fabry disease and in 30 healthy controls. The study protocol combined 1H-MRS with cardiac cine imaging and LGE MRI in a single examination. RESULTS: Myocardial lipid content was not significantly elevated in Fabry disease (p = 0.225). Left ventricular (LV) mass was significantly higher in patients suffering from Fabry disease compared to controls (p = 0.019). Comparison of patients without signs of myocardial fibrosis in MRI (LGE negative; n = 12) to patients with signs of fibrosis (LGE positive; n = 18) revealed similar myocardial lipid content in both groups (p > 0.05), while the latter showed a trend towards elevated LV mass (p = 0.076). CONCLUSIONS: This study demonstrates the potential of lipid metabolic investigation embedded in a comprehensive examination of cardiac morphology and function in Fabry disease. There was no evidence that lysosomal storage of sphingolipids influences cardiac lipid content as measured by 1H-MRS. Finally, the authors share the opinion that a comprehensive cardiac examination including three subsections (LGE; 1H-MRS; T1 mapping), could hold the highest potential for the final assessment of early and late myocardial changes in Fabry disease.
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Cardiomiopatías/metabolismo , Enfermedad de Fabry/diagnóstico , Imagen por Resonancia Cinemagnética/métodos , Espectroscopía de Resonancia Magnética/métodos , Miocardio/metabolismo , Esfingolípidos/metabolismo , Adolescente , Adulto , Anciano , Cardiomiopatías/diagnóstico , Cardiomiopatías/etiología , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Miocardio/patología , Factores de Tiempo , Función Ventricular Izquierda , Adulto JovenAsunto(s)
Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Insuficiencia Renal Crónica , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Humanos , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Naftiridinas , Insuficiencia Renal Crónica/tratamiento farmacológicoRESUMEN
Expression of proximal tubular organic anion transporters Oat1 and Oat3 is reduced by PGE2 after renal ischemia and reperfusion (I/R) injury. We hypothesized that impaired expression of Oat1/3 is decisively involved in the deterioration of renal function after I/R injury. Therefore, we administered probenecid, which blocks proximal tubular indomethacin uptake, to abolish the indomethacin-mediated restoration of Oat1/3 regulation and its effect on renal functional and morphological outcome. Ischemic acute kidney injury (iAKI) was induced in rats by bilateral clamping of renal arteries for 45 min with 24-h follow-up. Low-dose indomethacin (1 mg/kg) was given intraperitoneally (ip) at the end of ischemia. Probenecid (50 mg/kg) was administered ip 20 min later. Indomethacin restored the expression of Oat1/3, PAH net secretion, and PGE2 clearance. Additionally, indomethacin improved kidney function as measured by glomerular filtration rate (GFR), renal perfusion as determined by corrected PAH clearance, and morphology, whereas it reduced renal cortical apoptosis and nitric oxide production. Notably, indomethacin did not affect inflammation parameters in the kidneys (e.g., monocyte chemoattractant protein-1, ED1+ cells). On the other hand, probenecid blocked the indomethacin-induced restoration of Oat1/3 and moreover abrogated all beneficial effects. Our study indicates that the beneficial effect of low-dose indomethacin in iAKI is not due to its anti-inflammatory potency, but in contrast to its restoration of Oat1/3 expression and/or general renal function. Inhibition of proximal tubular indomethacin uptake abrogates the beneficial effect of indomethacin by resetting the PGE2-mediated Oat1/3 impairment, thus reestablishing renal damage. This provides evidence for a mechanistic effect of Oat1/3 in a new model of the induction of renal damage after iAKI.
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Lesión Renal Aguda/metabolismo , Isquemia/tratamiento farmacológico , Proteína 1 de Transporte de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/fisiopatología , Animales , Modelos Animales de Enfermedad , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Indometacina/administración & dosificación , Indometacina/farmacología , Isquemia/metabolismo , Riñón/metabolismo , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismoRESUMEN
Guidelines for the reduction of cholesterol to prevent atherosclerotic vascular events were recently released by the American Heart Association and the American College of Cardiology. The authors claim to refer entirely to evidence from randomized controlled trials, thereby confining their guidelines to statins as the primary therapeutic option. The guidelines derived from these trials do not specify treatment goals, but refer to the percentage of cholesterol reduction by statin medication with low, moderate, and high intensity. However, these targets are just as little tested in randomized trials as are the cholesterol goals derived from clinical experience. The same applies to the guidelines of the four patient groups which are defined by vascular risk. No major statin trial has included patients on the basis of their global risk; thus the allocation criteria are also arbitrarily chosen. These would actually lead to a significant increase in the number of patients to be treated with high or maximum dosages of statins. Also, adhering to dosage regulations instead of cholesterol goals contradicts the principles of individualized patient care. The option of the new risk score to calculate lifetime risk up to the age of 80 years in addition to the 10-year risk can be appreciated. Unfortunately it is not considered in the therapeutic recommendations provided, despite evidence from population and genetic studies showing that even a moderate lifetime reduction of low-density lipoprotein (LDL) cholesterol or non-HDL cholesterol has a much stronger effect than an aggressive treatment at an advanced age. In respect to secondary prevention, the new American guidelines broadly match the European guidelines. Thus, the involved societies from Germany, Austria and Switzerland recommend continuing according to established standards, such as the EAS/ESC guidelines.
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Anticolesterolemiantes/administración & dosificación , Aterosclerosis/sangre , Aterosclerosis/prevención & control , Dietoterapia/normas , Hipercolesterolemia/sangre , Hipercolesterolemia/prevención & control , Guías de Práctica Clínica como Asunto , Austria , Cardiología/normas , Humanos , Factores de Riesgo , SuizaRESUMEN
AIMS/HYPOTHESIS: A previous study in Dutch dialysis patients showed no survival difference between patients with diabetes as primary renal disease and those with diabetes as a co-morbid condition. As this was not in line with our hypothesis, we aimed to verify these results in a larger international cohort of dialysis patients. METHODS: For the present prospective study, we used data from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry. Incident dialysis patients with data on co-morbidities (n = 15,419) were monitored until kidney transplantation, death or end of the study period (5 years). Cox regression was performed to compare survival for patients with diabetes as primary renal disease, patients with diabetes as a co-morbid condition and non-diabetic patients. RESULTS: Of the study population, 3,624 patients (24%) had diabetes as primary renal disease and 1,193 (11%) had diabetes as a co-morbid condition whereas the majority had no diabetes (n = 10,602). During follow-up, 7,584 (49%) patients died. In both groups of diabetic patients mortality was higher compared with the non-diabetic patients. Mortality was higher in patients with diabetes as primary renal disease than in patients with diabetes as a co-morbid condition, adjusted for age, sex, country and malignancy (HR 1.20, 95% CI 1.10, 1.30). An analysis stratified by dialysis modality yielded similar results. CONCLUSIONS/INTERPRETATION: Overall mortality was significantly higher in patients with diabetes as primary renal disease compared with those with diabetes as a co-morbid condition. This suggests that survival in diabetic dialysis patients is affected by the extent to which diabetes has induced organ damage.
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Diabetes Mellitus/mortalidad , Enfermedades Renales/mortalidad , Diálisis Renal/estadística & datos numéricos , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards 'hard' clinical end-points in comparison with the natural course of the disease. METHODS: A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain. RESULTS: During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min(-1) per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry. CONCLUSION: Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease.
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Muerte Súbita Cardíaca , Terapia de Reemplazo Enzimático , Enfermedad de Fabry/tratamiento farmacológico , Isoenzimas/uso terapéutico , Fallo Renal Crónico/diagnóstico , Accidente Cerebrovascular/diagnóstico , alfa-Galactosidasa/uso terapéutico , Adulto , Estudios de Cohortes , Progresión de la Enfermedad , Enfermedad de Fabry/diagnóstico , Femenino , Tasa de Filtración Glomerular , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Enfermedad de Fabry , Genotipo , Humanos , Mutación , Polimorfismo Genético , alfa-Galactosidasa/genéticaRESUMEN
Fabry's disease is an X-chromosome linked lysosomal storage disorder with α-galactosidase A deficiency and subsequent multiple organ involvement. An early and common symptom also in later stages of the disease is pain. This pain depends on various precipitating factors and can severely compromise the quality of life. So-called Fabry crises can lead to the necessity for intensive care treatment. The pain can be classified as predominantly neuropathic and is difficult to treat. In addition, medication has to be adjusted to concomitant cardiac and renal involvement in Fabry's disease. This review gives guidance for pain therapy in Fabry's disease based on the available evidence and on experience.
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Analgésicos/uso terapéutico , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/terapia , Neuralgia/etiología , Neuralgia/terapia , Enfermedad de Fabry/diagnóstico , Humanos , Neuralgia/diagnósticoRESUMEN
BACKGROUND: Apolipoprotein A-IV (apoA-IV) is an anti-atherogenic and anti-oxidative plasma glycoprotein involved in reverse cholesterol transport. The aim of this study was to examine the association between apoA-IV and all-cause mortality, cardiovascular endpoints and parameters of protein-energy wasting and nutrition in haemodialysis patients. METHODS: This post hoc analysis was performed in the German Diabetes Dialysis Study (4D Study) evaluating atorvastatin in 1255 haemodialysis patients with type 2 diabetes mellitus, followed for a median of 4 years. The association between apoA-IV and relevant outcomes was analysed using Cox proportional hazards regression analyses. Body mass index (BMI) was used as a marker of protein-energy wasting. In addition, a definition of extended wasting was applied, combining median values of BMI, serum albumin, creatinine and sensitive C-reactive protein, to classify patients. RESULTS: Mean (±SD) apoA-IV concentration was 49.8 ± 14.2 mg dL(-1). Age- and gender-adjusted apoA-IV concentrations were strongly associated with the presence of congestive heart failure at baseline [odds ratio = 0.81, 95% confidence interval (CI) 0.74-0.88 per 10 mg dL(-1) increase; P < 0.001). During the prospective follow-up, the strongest association was found for all-cause mortality [hazard ratio (HR) = 0.89, 95% CI 0.85-0.95, P = 0.001), which was mainly because of patients with BMI > 23 kg m(-2) (HR = 0.87, 95% CI 0.82-0.94, P < 0.001) and those in the nonwasting group according to the extended definition (HR = 0.89, 95% CI 0.84-0.96, P = 0.001). This association remained significant after additionally adjusting for parameters associated with apoA-IV at baseline. Further associations were observed for sudden cardiac death. ApoA-IV was less strongly associated with atherogenic events such as myocardial infarction. CONCLUSIONS: Low apoA-IV levels seem to be a risk predictor of all-cause mortality and sudden cardiac death. This association might be modified by nutritional status.
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Apolipoproteínas A/sangre , Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Fallo Renal Crónico , Diálisis Renal , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antioxidantes/metabolismo , Índice de Masa Corporal , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Proteínas Portadoras/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/mortalidad , Metabolismo Energético , Métodos Epidemiológicos , Femenino , Alemania/epidemiología , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/etiología , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Estado Nutricional , Evaluación de Procesos y Resultados en Atención de Salud , Modelos de Riesgos Proporcionales , Diálisis Renal/mortalidad , Diálisis Renal/estadística & datos numéricos , Factores Sexuales , Adulto JovenRESUMEN
The timing of the start of dialysis in elderly patients is driven by the desire to optimize the quantity and quality of life. Limited data exist on how the level of renal function, and uraemic signs and symptoms can be used to determine when dialysis should be initiated in elderly patients. EQUAL, an international prospective cohort study, aims to address these issues. To this end, it will enroll 3500 patients >65 years of age with CKD of various aetiologies under the care of nephrologists. These patients will be followed until death, discharge from the nephrology clinic to primary care or until the end of the observation period after 4 years of follow-up. At the time of enrollment, patients must have an estimated glomerular filtration rate (eGFR) of 20 mL/min/1.73 m(2) or lower, but should not yet be on dialysis. Standardized data collection will include demographics, lifestyle, comorbidities, uraemic signs and symptoms, nutritional status, medication and routine blood and urine biochemistry. It will also comprise quality of life data, information on decision making including patients preferences and patients satisfaction.
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Calidad de Vida , Diálisis Renal , Insuficiencia Renal Crónica/terapia , Comorbilidad , Europa (Continente) , Tasa de Filtración Glomerular , Humanos , Insuficiencia Renal Crónica/patología , Factores de RiesgoRESUMEN
Lysosomal storage disorders (LSD) are rare diseases, caused by inherited deficiencies of lysosomal enzymes/transporters, that affect 1 in 7000 to 1 in 8000 newborns. Individuals with LSDs face long diagnostic journeys during which debilitating and life-threatening events can occur. Clinical trials and classical descriptions of LSDs typically focus on common manifestations, which are not representative of the vast phenotypic heterogeneity encountered in real-world experience. Additionally, recognizing that there was a limited understanding of the natural history, disease progression, and real-world clinical outcomes of rare LSDs, a collaborative partnership was pioneered 30 years ago to address these gaps. The Rare Disease Registries (RDR) (for Gaucher, Fabry, Mucopolysaccharidosis type I, and Pompe), represent the largest observational database for these LSDs. Over the past thirty years, data from the RDRs have helped to inform scientific understanding and the development of comprehensive monitoring and treatment guidelines by creating a framework for data collection and establishing a standard of care, with an overarching goal to improve the quality of life of affected patients. Here, we highlight the history, process, and impact of the RDRs, and discuss the lessons learned and future directions.
Asunto(s)
Enfermedades por Almacenamiento Lisosomal , Enfermedades Raras , Humanos , Recién Nacido , Enfermedades por Almacenamiento Lisosomal/tratamiento farmacológico , Lisosomas , Calidad de Vida , Sistema de RegistrosRESUMEN
Renal organic cation transporters are downregulated by nitric oxide (NO) in rat endotoxemia. NO generated by inducible NO synthase (iNOS) is substantially increased in the renal cortex after renal ischemia-reperfusion (I/R) injury. Therefore, we investigated the effects of iNOS-specific NO inhibition on the expression of the organic cation transporters rOct1 and rOct2 (Slc22a1 and Slc22a2, respectively) after I/R injury both in vivo and in vitro. In vivo, N(6)-(1-iminoethyl)-L-lysine (L-NIL) completely inhibited NO generation after I/R injury. Moreover, L-NIL abolished the ischemia-induced downregulation of rOct1 and rOct2 as determined by qPCR and Western blotting. Functional evidence was obtained by measuring the fractional excretion (FE) of the endogenous organic cation serotonin. Concordant with the expression of the rate-limiting organic cation transporter, the FE of serotonin decreased after I/R injury and was totally abolished by L-NIL. In vitro, ischemia downregulated both rOct1 and rOct2, which were also abolished by L-NIL; the same was true for the uptake of the organic cation MPP. We showed that renal I/R injury downregulates rOct1 and rOct2, which is most probably mediated via NO. In principle, this may be an autocrine effect of proximal tubular epithelial cells. We conclude that rOct1, or rOct1 and rOct2 limit the rate of the renal excretion of serotonin.
Asunto(s)
Proteínas de Transporte de Catión/metabolismo , Enfermedades Renales/metabolismo , Riñón/metabolismo , Óxido Nítrico/farmacología , Daño por Reperfusión/metabolismo , 1-Metil-4-fenilpiridinio/metabolismo , Animales , Western Blotting , Proteínas de Transporte de Catecolaminas en la Membrana Plasmática/biosíntesis , Línea Celular , Regulación hacia Abajo , Inhibidores Enzimáticos/farmacología , Femenino , Riñón/efectos de los fármacos , Corteza Renal/efectos de los fármacos , Corteza Renal/metabolismo , Pruebas de Función Renal , Lisina/análogos & derivados , Lisina/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Transportadores de Anión Orgánico Sodio-Independiente/biosíntesis , Proteínas de Transporte de Catión Orgánico/biosíntesis , Transportador 2 de Cátion Orgánico , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Serotonina/orinaRESUMEN
Heart failure with preserved ejection fraction (HFpEF) is highly prevalent in patients on maintenance haemodialysis (HD) and lacks effective treatment. We investigated the effect of spironolactone on cardiac structure and function with a specific focus on diastolic function parameters. The MiREnDa trial examined the effect of 50 mg spironolactone once daily versus placebo on left ventricular mass index (LVMi) among 97 HD patients during 40 weeks of treatment. In this echocardiographic substudy, diastolic function was assessed using predefined structural and functional parameters including E/e'. Changes in the frequency of HFpEF were analysed using the comprehensive 'HFA-PEFF score'. Complete echocardiographic assessment was available in 65 individuals (59.5 ± 13.0 years, 21.5% female) with preserved left ventricular ejection fraction (LVEF > 50%). At baseline, mean E/e' was 15.2 ± 7.8 and 37 (56.9%) patients fulfilled the criteria of HFpEF according to the HFA-PEFF score. There was no significant difference in mean change of E/e' between the spironolactone group and the placebo group (+ 0.93 ± 5.39 vs. + 1.52 ± 5.94, p = 0.68) or in mean change of left atrial volume index (LAVi) (1.9 ± 12.3 ml/m2 vs. 1.7 ± 14.1 ml/m2, p = 0.89). Furthermore, spironolactone had no significant effect on mean change in LVMi (+ 0.8 ± 14.2 g/m2 vs. + 2.7 ± 15.9 g/m2; p = 0.72) or NT-proBNP (p = 0.96). Treatment with spironolactone did not alter HFA-PEFF score class compared with placebo (p = 0.63). Treatment with 50 mg of spironolactone for 40 weeks had no significant effect on diastolic function parameters in HD patients.The trial has been registered at clinicaltrials.gov (NCT01691053; first posted Sep. 24, 2012).