RESUMEN
Monoclonal immunoglobulin M-associated type I cryoglobulinaemia is poorly characterised. We screened 534 patients with monoclonal IgM disorders over a 9-year period and identified 134 patients with IgM type I cryoglobulins. Of these, 76% had Waldenström macroglobulinaemia (WM), 5% had other non-Hodgkin lymphoma (NHL) and 19% had IgM monoclonal gammopathy of undetermined significance (MGUS). Clinically relevant IgM-associated disorders (including cold agglutinin disease [CAD], anti-MAG antibodies, amyloidosis and Schnitzler syndrome) coexisted in 31%, more frequently in MGUS versus WM/NHL (72% vs. 22%/29%, p < 0.001). The majority of those with cryoglobulins and coexistent CAD/syndrome had the molecular characteristics of a CAD clone (wild-type MYD88 in 80%). A half of all patients had active manifestations at cryoglobulin detection: vasomotor (22%), cutaneous (16%), peripheral neuropathy (22%) and hyperviscosity (9%). 16/134 required treatment for cryoglobulin-related symptoms alone at a median of 38 days (range: 6-239) from cryoglobulin detection. At a median follow-up of 3 years (range: 0-10), 3-year cryoglobulinaemia-treatment-free survival was 77% (95% CI: 68%-84%). Age was the only predictor of overall survival. Predictors of cryoglobulinaemia-related treatment/death were hyperviscosity (HR: 73.01; 95% CI: 15.62-341.36, p < 0.0001) and cutaneous involvement (HR: 2.95; 95% CI: 1.13-7.71, p = 0.028). Type I IgM cryoglobulinaemia is more prevalent than previously described in IgM gammopathy and should be actively sought.
Asunto(s)
Crioglobulinemia , Linfoma de Células B , Gammopatía Monoclonal de Relevancia Indeterminada , Macroglobulinemia de Waldenström , Humanos , Crioglobulinas , Crioglobulinemia/etiología , Macroglobulinemia de Waldenström/patología , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Inmunoglobulina M , Anticuerpos Monoclonales , ParaproteínasRESUMEN
Here we present the case of a 28-year-old man with X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection and neoplasia (XMEN) disease. He presented with immune thrombocytopenia within 1 year after successful autologous hematopoietic stem cell transplantation for recurrent EBV-associated classical Hodgkin lymphoma (CHL). The combination of EBV- associated malignancy, autoimmunity, recurrent airway infections at young age and bronchiectasis, prompted immunological investigation for an inborn error of immunity (IEI). Genetic testing revealed XMEN disease. XMEN disease is characterized by a glycosylation defect due to mutations in the MAGT1 gene. Germline mutations in the MAGT1 gene disrupt glycosylation of the NKG2D receptor in immune cells, including natural killer and CD8-positive T cells, vital for immune surveillance, especially against EBV. Consequently, individuals with XMEN disease, are prone to EBV-associated lymphoproliferative disorders in addition to auto-immunity. Early recognition of adult onset IEI-related B-lymphoproliferative disorders, including CHL is of vital importance for treatment decisions, including (allogeneic) haematopoietic stem cell transplantation and family screening.
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Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare heterogeneous disease in which treatment must be initiated early to prevent irreversible organ damage and death. There are several diseases that can mimic AAV, even in the presence of positive ANCA serology and/or histological evidence of vasculitis, as demonstrated in this case series. We reflect on the diagnostic approach of patients with AAV and provide an overview of AAV-mimicking diseases that can be considered in patients with atypical disease presentation or course.
RESUMEN
Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE) that occurs in about half of patients. LN is characterized by glomerular deposition of immune complexes, leading to subendothelial, mesangial and subepithelial electron dense deposits, triggering immune cell infiltration and glomerular as well as tubulointerstitial injury. Monocytes and macrophages are abundantly present in inflammatory lesions, both in glomeruli and the tubulointerstitium. Here we discuss how monocytes and macrophages are involved in this process and how monocytes and macrophages may represent specific therapeutic targets to control LN.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Humanos , Riñón/patología , Nefritis Lúpica/terapia , Glomérulos Renales , Complejo Antígeno-AnticuerpoRESUMEN
We report a case of intestinal lesions in a patient with a history of lupus nephritis and renal transplantation. Biopsy revealed an EBV-driven post-transplant lymphoproliferative disease (PTLD). An EBV-driven PTLD is a major complication after renal transplantation and is an important differential diagnostic consideration in the follow-up of renal transplant recipients.
RESUMEN
BACKGROUND: A novel autoinflammatory syndrome was recently described in male patients who harbored somatic mutations in the X-chromosomal UBA1 gene. These patients were characterized by adult-onset, treatment-refractory inflammation with fever, cytopenia, dysplastic bone marrow, vacuoles in myeloid and erythroid progenitor cells, cutaneous and pulmonary inflammation, chondritis, and vasculitis, which is abbreviated as VEXAS. OBJECTIVE: This study aimed to (retrospectively) diagnose VEXAS in patients who had previously been registered as having unclassified autoinflammation. We furthermore aimed to describe clinical experiences with this multifaceted, complex disease. METHODS: A systematic reanalysis of whole-exome sequencing data from a cohort of undiagnosed patients with autoinflammation from academic hospitals in The Netherlands was performed. When no sequencing data were available, targeted Sanger sequencing was applied in cases with high clinical suspicion of VEXAS. RESULTS: A total of 12 male patients who carried mutations in UBA1 were identified. These patients presented with adult-onset (mean age 67 years, range 47-79 years) autoinflammation with systemic symptoms, elevated inflammatory parameters, and multiorgan involvement, most typically involving the skin and bone marrow. Novel features of VEXAS included interstitial nephritis, cardiac involvement, stroke, and intestinal perforation related to treatment with tocilizumab. Although many types of treatment were initiated, most patients became treatment-refractory, with a high mortality rate of 50%. CONCLUSION: VEXAS should be considered in the differential diagnosis of males with adult-onset autoinflammation characterized by systemic symptoms and multiorgan involvement. Early diagnosis can prevent unnecessary diagnostic procedures and provide better prognostic information and more suitable treatment options, including stem cell transplantation.
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Enfermedades Autoinflamatorias Hereditarias/genética , Síndromes Mielodisplásicos/genética , Enfermedades Cutáneas Genéticas/genética , Enzimas Activadoras de Ubiquitina/genética , Adulto , Edad de Inicio , Anciano , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/diagnóstico , Países Bajos , Estudios Retrospectivos , Enfermedades Cutáneas Genéticas/diagnósticoRESUMEN
Sodium restriction may potentially reduce iodine intake. This study aimed to determine the effect of sodium restriction (dietary counseling) on 24-h urinary iodine excretion. Diuretics provide an alternative to sodium restriction and are frequently added to sodium restriction, so the effects of hydrochlorothiazide (50 mg daily) and combined therapy were also studied. We performed a post-hoc analysis of a Dutch multi-center, randomized cross-over trial in 45 patients with diabetic kidney disease with a mean age of 65 ± 9 years, mean eGFR of 65 ± 27 mL/min/1.73 m2, median albuminuria of 648 [230-2008] mg/24 h and 84% were male. During regular sodium intake with placebo, mean 24 h urinary sodium and iodine excretion were 224 ± 76 mmol/24 h and 252 ± 94 ug/24 h, respectively (r = 0.52, p < 0.001). Mean iodine excretion did not change significantly if sodium restriction and hydrochlorothiazide were applied separately; mean difference -8 ug/day (95% CI -38, 22; p = 0.6) and 14 ug/day (95% CI -24, 52; p = 0.5), respectively. Combined therapy induced a significant decrease in mean iodine excretion (-37 ug/day; 95% CI -67, -7; p = 0.02), yet this was not seen to a clinically meaningful level. The number of patients with an estimated intake below recommended daily allowances did not differ significantly between the four treatment periods (p = 0.3). These findings show that sodium restriction is not a risk factor for iodine deficiency.
Asunto(s)
Nefropatías Diabéticas/orina , Dieta Hiposódica/efectos adversos , Hidroclorotiazida/administración & dosificación , Yodo/orina , Sodio en la Dieta/análisis , Anciano , Estudios Cruzados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sodio/orinaRESUMEN
Reduction of residual albuminuria during single-agent renin-angiotensin-aldosterone blockade is accompanied by improved cardiorenal outcomes in CKD. We studied the individual and combined effects of the vitamin D receptor activator paricalcitol (PARI) and dietary sodium restriction on residual albuminuria in CKD. In a multicenter, randomized, placebo (PLAC)-controlled, crossover trial, 45 patients with nondiabetic CKD stages 1-3 and albuminuria >300 mg/24 h despite ramipril at 10 mg/d and BP<140/90 mmHg were treated for four 8-week periods with PARI (2 µg/d) or PLAC, each combined with a low-sodium (LS) or regular sodium (RS) diet. We analyzed the treatment effect by linear mixed effect models for repeated measurements. In the intention-to-treat analysis, albuminuria (geometric mean) was 1060 (95% confidence interval, 778 to 1443) mg/24 h during RS + PLAC and 990 (95% confidence interval, 755 to 1299) mg/24 h during RS + PARI (P=0.20 versus RS + PLAC). LS + PLAC reduced albuminuria to 717 (95% confidence interval, 512 to 1005) mg/24 h (P<0.001 versus RS + PLAC), and LS + PARI reduced albuminuria to 683 (95% confidence interval, 502 to 929) mg/24 h (P<0.001 versus RS + PLAC). The reduction by PARI beyond the effect of LS was nonsignificant (P=0.60). In the per-protocol analysis restricted to participants with ≥95% compliance with study medication, PARI did provide further albuminuria reduction (P=0.04 LS + PARI versus LS + PLAC). Dietary adherence was good as reflected by urinary excretion of 174±64 mmol Na+ per day in the combined RS groups and 108±61 mmol Na+ per day in the LS groups (P<0.001). In conclusion, moderate dietary sodium restriction substantially reduced residual albuminuria during fixed dose angiotensin-converting enzyme inhibition. The additional effect of PARI was small and nonsignificant.
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Albuminuria/etiología , Albuminuria/terapia , Dieta Hiposódica , Ergocalciferoles/uso terapéutico , Receptores de Calcitriol/fisiología , Insuficiencia Renal Crónica/complicaciones , Terapia Combinada , Estudios Cruzados , Método Doble Ciego , HumanosRESUMEN
Fibroblast growth factor 23 (FGF-23) rises progressively in chronic kidney disease and is associated with adverse cardiovascular outcomes. FGF-23 putatively induces volume retention by upregulating the sodium-chloride cotransporter (NCC). We studied whether, conversely, interventions in volume status affect FGF-23 concentrations.We performed a post hoc analysis of 1) a prospective saline infusion study with 12 patients with arterial hypertension who received 2âL of isotonic saline over 4 hours, and 2) a randomized controlled trial with 45 diabetic nephropathy (DN) patients on background angiotensin-converting enzyme -inhibition (ACEi), who underwent 4 6-week treatment periods with add-on hydrochlorothiazide (HCT) or placebo, combined with regular sodium (RS) or low sodium (LS) diet in a cross-over design. Plasma C-terminal FGF-23 was measured by ELISA (Immutopics) after each treatment period in DN and before and after saline infusion in hypertensives.The patients with arterial hypertension were 45â±â13 (meanâ±âSD) years old with an estimated glomerular filtration rate (eGFR) of 101â±â18âmL/min/1.73âm. Isotonic saline infusion did not affect FGF-23 (before infusion: 68 median [first to third quartile: 58-97] relative unit (RU)/mL, after infusion: 67 [57-77]âRU/mL, Pâ=â0.37). DN patients were 65â±â9 years old. During ACEiâ+âRS treatment, eGFR was 65â±â25âmL/min/1.73âm and albuminuria 649âmg/d (230-2008âmg/d). FGF23 level was 94 (73-141)âRU/mL during ACEi therapy. FGF-23 did not change significantly by add-on HCT (99 [74-148]âRU/mL), LS diet (99 [75-135]âRU/mL), or their combination (111 [81-160]âRU/mL, Pâ=â0.15).Acute and chronic changes in volume status did not materially change FGF-23 in hypertensive patients and DN, respectively. Our data do not support a direct feedback loop between volume status and FGF-23 in hypertension or DN.
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Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/terapia , Dieta Hiposódica , Diuréticos/uso terapéutico , Factores de Crecimiento de Fibroblastos/sangre , Hidroclorotiazida/uso terapéutico , Hipertensión/sangre , Hipertensión/terapia , Soluciones Isotónicas/administración & dosificación , Anciano , Estudios Cruzados , Método Doble Ciego , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND: Plasma cholesteryl ester transfer (CET), reflecting transfer of cholesteryl esters from high density lipoproteins (HDL) towards apolipoprotein B-containing lipoproteins, may promote atherosclerosis development, and is elevated in Type 2 diabetes mellitus (T2DM). We determined the extent to which the relationship of plasma CET with very low density lipoprotein (VLDL) and low density lipoprotein (LDL) subfractions is modified in T2DM. MATERIALS AND METHODS: Plasma CET, cholesteryl ester transfer protein (CETP) mass, as well as VLDL and LDL subfractions (nuclear magnetic resonance spectroscopy) were determined in 62 patients with T2DM and 53 nondiabetic subjects. RESULTS: Plasma CET and CETP mass were increased in T2DM, coinciding higher triglycerides and large VLDL particles (all P < 0·02). Plasma CET was positively related to the VLDL and the LDL particle concentration in age-, sex- and diabetes status-adjusted analysis (both P < 0·001). Multivariable linear regression analysis demonstrated an independent positive interaction between the presence of T2DM and the VLDL concentration on plasma CET (ß = 0·238, P = 0·033). The relationship of plasma CET with the VLDL concentration was also positively modified by plasma glucose (ß = 0·211, P = 0·004) and glycated haemoglobin (ß = 0·190, P = 0·012). Of the individual VLDL subfractions, a positive interaction of diabetes status with large VLDL on plasma CET was observed (ß = 0·280, P = 0·003). Neither the relationship of the LDL particle concentration nor of CETP mass with plasma CET was modified by the presence of T2DM (P > 0·15). CONCLUSION: Abnormalities in the concentration and composition of large VLDL particles are likely to contribute to elevated plasma CET in T2DM.
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Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , VLDL-Colesterol/fisiología , Diabetes Mellitus Tipo 2/metabolismo , Estudios de Casos y Controles , LDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Espectroscopía de Resonancia Magnética , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Compuestos de Sulfonilurea/uso terapéuticoRESUMEN
BACKGROUND: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patients. Previous studies linked high fibroblast growth factor 23 (FGF-23) levels with volume overload; others linked higher serum phosphate levels with impaired RAAS-blockade efficacy. We hypothesized that FGF-23 reduces the capacity of dietary sodium restriction to potentiate RAAS blockade, impairing the antiproteinuric effect. STUDY DESIGN: Post hoc analysis of cohort data from a randomized crossover trial with two 6-week study periods comparing proteinuria after a regular-sodium diet with proteinuria after a low-sodium diet, both during background angiotensin-converting enzyme inhibition. SETTING & PARTICIPANTS: 47 nondiabetic patients with CKD with residual proteinuria (median protein excretion, 1.9 [IQR, 0.8-3.1] g/d; mean age, 50±13 [SD] years; creatinine clearance, 69 [IQR, 50-110] mL/min). PREDICTOR: Plasma carboxy-terminal FGF-23 levels. OUTCOMES: Difference in residual proteinuria at the end of the regular-sodium versus low-sodium study period. Residual proteinuria during the low-sodium diet period adjusted for proteinuria during the regular-sodium diet period. RESULTS: Higher baseline FGF-23 level was associated with reduced antiproteinuric response to dietary sodium restriction (standardized ß=-0.46; P=0.001; model R(2)=0.71). For every 100-RU/mL increase in FGF-23 level, the antiproteinuric response to dietary sodium restriction was reduced by 10.6%. Higher baseline FGF-23 level was a determinant of more residual proteinuria during the low-sodium diet (standardized ß=0.27; P=0.003) in linear regression analysis adjusted for baseline proteinuria (model R(2)=0.71). There was no interaction with creatinine clearance (P interaction=0.5). Baseline FGF-23 level did not predict changes in systolic or diastolic blood pressure upon intensified antiproteinuric treatment. LIMITATIONS: Observational study, limited sample size. CONCLUSIONS: FGF-23 levels are associated independently with impaired antiproteinuric response to sodium restriction in addition to RAAS blockade. Future studies should address whether FGF-23-lowering strategies may further optimize proteinuria reduction by RAAS blockade combined with dietary sodium restriction.
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Aldosterona/sangre , Dieta Hiposódica , Factores de Crecimiento de Fibroblastos/sangre , Proteinuria/sangre , Sistema Renina-Angiotensina/fisiología , Cloruro de Sodio Dietético/sangre , Adulto , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Biomarcadores/sangre , Estudios Cruzados , Dieta Hiposódica/tendencias , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Masculino , Persona de Mediana Edad , Proteinuria/dietoterapia , Proteinuria/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacosRESUMEN
BACKGROUND: Reducing sodium intake can prevent cardiovascular complications and further decline of kidney function in patients with chronic kidney disease. However, the vast majority of patients fail to reach an adequate sodium intake, and little is known about why they do not succeed. PURPOSE: This study aims to identify perceived barriers and support strategies for reducing sodium intake among both patients with chronic kidney disease and health-care professionals. METHOD: A purposive sample of 25 patients and 23 health-care professionals from 4 Dutch medical centers attended 8 focus groups. Transcripts were analyzed thematically and afterwards organized according to the phases of behavior change of self-regulation theory. RESULTS: Multiple themes emerged across different phases of behavior change, including the patients' lack of practical knowledge and intrinsic motivation, the maladaptive illness perceptions and refusal skills, the lack of social support and feedback regarding disease progression and sodium intake, and the availability of low-sodium foods. CONCLUSIONS: The results indicate the need for the implementation of support strategies that target specific needs of patients across the whole process of changing and maintaining a low-sodium diet. Special attention should be paid to supporting patients to set sodium-related goals, strengthening intrinsic motivation, providing comprehensive and practical information (e.g., about hidden salt in products), increasing social support, stimulating the self-monitoring of sodium intake and disease progression, and building a supportive patient-professional relationship that encompasses shared decision making and coaching. Moreover, global programs should be implemented to reduce sodium levels in processed foods, introduce sodium-related product labels, and increase consumer awareness.
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Personal de Salud/estadística & datos numéricos , Motivación , Insuficiencia Renal Crónica/terapia , Sodio/administración & dosificación , Adulto , Anciano , Toma de Decisiones , Femenino , Grupos Focales , Humanos , Masculino , Persona de Mediana Edad , Percepción , Relaciones Profesional-Paciente , Apoyo SocialRESUMEN
Hypertension and proteinuria are important mediators of renal damage. Despite therapeutic interventions, the number of patients with end stage renal disease steadily increases. Hydrogen sulfide (H(2)S) is an endogenously produced gasotransmitter with vasodilatory, anti-inflammatory and antioxidant properties. These beneficial characteristics make H(2)S an attractive candidate for pharmacological use in hypertensive renal disease. We investigated the protective properties of H(2)S in angiotensin II (Ang II)-induced hypertensive renal disease in rats. Treatment with the H(2)S donor NaHS and major H(2)S metabolite sodium thiosulfate (STS) during three weeks of Ang II infusion reduced hypertension, proteinuria, oxidative stress and renal functional and structural deterioration. In an ex vivo isolated perfused kidney setup, NaHS, but not STS, reduced intrarenal pressure. The effect of NaHS could partially be explained by its activation of the ATP-sensitive potassium channels. In conclusion, treatment with H(2)S attenuates Ang II-associated functional and structural renal deterioration, suggesting that intervention in H(2)S production pathways has potential therapeutic benefit and might be a valuable addition to the already existing antihypertensive and renoprotective therapies.
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Angiotensina II/fisiología , Hipertensión/inducido químicamente , Riñón/efectos de los fármacos , Proteinuria/inducido químicamente , Tiosulfatos/farmacología , Animales , Secuencia de Bases , Cartilla de ADN , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
BACKGROUND: Reduction of dietary sodium intake or diuretic treatment increases renin-angiotensin-aldosterone system (RAAS) blockade efficacy in non-diabetic nephropathy. We aimed to investigate the effect of sodium restriction and the diuretic hydrochlorothiazide, separately and in combination, added to RAAS blockade on residual albuminuria in patients with type 2 diabetic nephropathy. METHODS: In this multicentre, double-blind, placebo-controlled, crossover randomised trial, we included patients with type 2 diabetic nephropathy. Main entry criteria were microalbuminaria or macroalbuminuria, and creatinine clearance of 30 mL/min or higher with less than 6 mL/min decline in the previous year. We tested the separate and combined effects of sodium restriction (dietary counselling in the outpatient setting) and hydrochlorothiazide (50 mg daily), added to standardised maximal angiotensin-converting enzyme (ACE) inhibition (lisinopril 40 mg daily), on albuminuria (primary endpoint). Patients were given hydrochlorothiazide (50 mg per day) or placebo during four treatment periods of 6 weeks. Both treatments were combined with regular sodium diet or sodium restriction (target sodium intake 50 mmol Na(+) per day). The 6-week treatment periods were done consecutively in a random order. Patients were randomised in blocks of two patients. The trial was analysed by intention to treat. The trial is registered with TrialRegister.nl, number 2366. FINDINGS: Of 89 eligible patients, 45 were included in the study. Both sodium restriction and hydrochlorothiazide significantly reduced albuminuria, irrespective of treatment sequence. Residual geometric mean albuminuria with baseline treatment was 711 mg per day (95% CI 485-1043); it was significantly reduced by sodium restriction (393 mg per day [258-599], p=0·0002), by hydrochlorothiazide (434 mg per day [306-618], p=0·0003), and to the greatest extent by their combination (306 mg per day [203-461], p<0·0001). Orthostatic complaints were present in two patients (4%) during baseline treatment, five (11%) during addition of sodium restriction, five (11%) during hydrochlorothiazide treatment, and 12 (27%) during combination treatment. No serious adverse events occurred. INTERPRETATION: We conclude that sodium restriction is an effective non-pharmacological intervention to increase RAAS blockade efficacy in type 2 diabetic nephropathy. FUNDING: None.
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Albuminuria/tratamiento farmacológico , Neuropatías Diabéticas/tratamiento farmacológico , Dieta Hiposódica , Diuréticos/uso terapéutico , Hidroclorotiazida/uso terapéutico , Sistema Renina-Angiotensina/efectos de los fármacos , Anciano , Albuminuria/dietoterapia , Presión Sanguínea , Neuropatías Diabéticas/dietoterapia , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a key regulator of low density lipoprotein (LDL) receptor processing, but the PCSK9 pathway may also be implicated in the metabolism of triglyceride-rich lipoproteins. Here we determined the relationship of plasma PCSK9 with very low density lipoprotein (VLDL) and LDL subfractions. DESIGN AND METHODS: The relationship of plasma PCSK9 (sandwich enzyme-linked immunosorbent assay) with 3 very low density lipoprotein (VLDL) and 3 low density lipoprotein (LDL) subfractions (nuclear magnetic resonance spectroscopy) was determined in 52 subjects (30 women). RESULTS: In age- and sex-adjusted analysis plasma PCSK9 was correlated positively with total cholesterol, non-high density lipoprotein cholesterol and LDL cholesterol (r=0.516 to 0.547, all p<0.001), as well as with triglycerides (r=0.286, p=0.044). PCSK9 was correlated with the VLDL particle concentration (r=0.336, p=0.017) and with the LDL particle concentration (r=0.362, p=0.010), but only the relationship with the LDL particle concentration remained significant in multivariable linear regression analysis. In an analysis which included the 3 LDL subfractions, PCSK9 was independently related to intermediate density lipoproteins (IDL) (p<0.001), but not to other LDL subfractions. CONCLUSIONS: This study suggests that plasma PCSK9 predominantly relates to IDL, a triglyceride-rich LDL subfraction. The PCSK9 pathway may affect plasma triglycerides via effects on the metabolism of triglyceride-rich LDL particles.
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Lipoproteínas IDL/sangre , Lipoproteínas VLDL/sangre , Proproteína Convertasas/sangre , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: The cholesterol esterifying enzyme, lecithin:cholesterol acyltransferase (LCAT), plays a key role in HDL maturation and remodeling. Myeloperoxidase (MPO) may compromise LCAT enzymatic activity. We tested the extent to which plasma LCAT activity is altered in acute myocardial infarction (MI) in conjunction with abnormal MPO levels. We also assessed the impact of LCAT and MPO on newly developed major adverse cardiovascular events (MACE). METHODS: Two-hundred one consecutive patients referred for acute chest pain of whom 134 had MI (95 with ST-elevation) participated. Forty-five new MACE were ascertained during 1203 (range 13-1745) days of follow-up among 185 patients. Plasma LCAT activity was measured using an exogenous substrate assay. MPO mass was assayed by chemiluminescent microparticle immunoassay. RESULTS: Plasma LCAT activity was decreased by 15%, coinciding with 7-fold increased MPO levels in acute MI patients vs. patients with non-cardiac chest pain (p < 0.001 for both; correlation: r = -0.343, p < 0.001). MI at admission was associated independently with both lower plasma LCAT activity and higher MPO (age- and sex-adjusted odds ratio per 1 SD increment: 0.46 (95% CI, 0.31-0.68), p < 0.001 and 7.58 (95% CI, 3.34-17.11), p < 0.001, respectively). In an analysis with LCAT and MPO together these associations were modestly attenuated. MPO mass (hazard ratio: 1.59 (95% CI, 1.15-2.19), p = 0.004), but not LCAT activity (hazard ratio: 0.87 (95% CI, 0.65-1.19), p = 0.39), predicted newly manifest MACE. CONCLUSION: In acute MI patients, plasma LCAT activity is decreased coinciding with increased MPO levels. Higher MPO but not lower LCAT activity prospectively predicts adverse cardiac outcome.
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Infarto del Miocardio/sangre , Peroxidasa/sangre , Fosfatidilcolina-Esterol O-Aciltransferasa/sangre , Anciano , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Infarto del Miocardio/complicacionesRESUMEN
BACKGROUND: The strong anti-oxidative properties of bilirubin largely explain its cardioprotective effects. Insulin resistance is featured by low circulating bilirubin. Thyroid hormone affects both bilirubin generation and its biliary transport, but it is unknown whether circulating bilirubin is associated with thyroid function in euthyroid subjects. Aim is to determine relationships of bilirubin with TSH, free T4 and free T3 in euthyroid subjects without type 2 diabetes mellitus (T2DM), and to assess whether such a relationship would be modified by the degree of insulin resistance. METHODS: Total bilirubin, TSH, free T4, free T3, glucose, insulin, lipids and transaminases were measured in 1854 fasting euthyroid subjects without T2DM, recruited from the general population (PREVEND cohort). Insulin resistance was assessed by homeostasis model assessment. RESULTS: Bilirubin was positively related to free T4 (ßâ=â0.116, P<0.001) and free T3 (ßâ=â0.078, Pâ=â0.001), but bilirubin was unrelated to TSH. The relationship of bilirubin with free T4 was modified by insulin resistance with a larger effect in more insulin resistant individuals (adjusted for age and sex: ßâ=â0.043, Pâ=â0.056 for interaction; additionally adjusted for smoking, alcohol intake, transaminases and total cholesterol (ßâ=â0.044, Pâ=â0.044 for interaction). The association of bilirubin with free T4 was also modified by high density lipoprotein cholesterol (age- and sex-adjusted: ßâ=â0.040, Pâ=â0.072). CONCLUSIONS: Low bilirubin relates to low free T4 in euthyroid non-diabetic subjects. Low normal free T4 may particularly confer low bilirubin in more insulin resistant individuals.
Asunto(s)
Antioxidantes/metabolismo , Bilirrubina/sangre , Resistencia a la Insulina/fisiología , Tiroxina/sangre , Adulto , Factores de Edad , Anciano , Bilirrubina/metabolismo , Transporte Biológico/fisiología , Femenino , Humanos , Insulina/sangre , Lípidos/sangre , Modelos Logísticos , Masculino , Persona de Mediana Edad , Países Bajos , Factores Sexuales , Glándula Tiroides/fisiología , Tirotropina/sangre , Tiroxina/metabolismo , Transaminasas/sangreRESUMEN
Despite advances in preventive therapy, prognosis in chronic kidney disease (CKD) is still grim. Clinical cohorts of CKD patients provide a strategic resource to identify factors that drive progression in the context of clinical care and to provide a basis for improvement of outcome. The combination with biobanking, moreover, provides a resource for fundamental and translational studies. In 2007, the Dutch government initiated and funded the String of Pearls Initiative (PSI), a strategic effort to establish infrastructure for disease-based biobanking in the University Medical Centres (UMCs) in the Netherlands, in a 4-year start-up period. CKD was among the conditions selected for biobanking, and this resulted in the establishment of the Biobank of Nephrological Diseases-NL (BIND-NL) cohort. Patients with CKD Stages 1-4 are eligible. The data architecture is designed to reflect routine care, with specific issues added for enrichment, e.g. questionnaires. Thus, the collected clinical and biochemical data are those required by prevailing guidelines for routine nephrology care, with a minimal dataset for all patients, and diagnosis-specific data for the diagnostic categories of primary and secondary glomerular disorders and adult dominant polycystic kidney disease, respectively. The dataset is supplemented by a biobank, containing serum, plasma, urine and DNA. The cohort will be longitudinally monitored, with yearly follow-up for clinical outcome. Future linking of the data to those from the national registries for renal replacement therapy is foreseen to follow the patients' lifeline throughout the different phases of renal disease and different treatment modalities. In the design of the data architecture, care was taken to ensure future exchangeability of data with other CKD cohorts by applying the data harmonization format of the Renal DataSHaPER, with a dataset based upon standardized indicator sets to facilitate collaboration with other CKD cohorts. Enrolment started in 2010, and over 2200 eligible patients have been enrolled in the different UMCs. Follow-up of enrolled patients has started, and enrolment will continue at a slower rate. The aggregation and standardization of clinical data and biosamples from large numbers of CKD patients will be a strategic resource not only for clinical and translational research, but also by its basis in routine clinical care for clinical governance and quality improvement projects.