Síndrome urémico hemolítico atípico

Síndrome urémico hemolítico es una entidad caracterizada por anemia hemolítica microangiopática no inmune, trombocitopenia, afectación renal y manifestaciones en diversos órganos como páncreas, corazón. Etiológicamente se reconoce el llamado síndrome urémico hemolítico típico (SUH), causado por infecciones por bacterias productoras de shigatoxina (STEC) cepas de E. coli y Shigella disenteriae y un mismo cuadro clínico con distintas repercusiones, lo provocan alteraciones genéticas por disregulación de la vía alterna del complemento y otras anomalías como la deficiencia de ciancobalamina o la diacylglycerolquinasa (DGKE) y constituyen el SUH atípico(SUHa).Fil: Sánchez Luceros, Analía Gabriela. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Dos Santos, Célia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Fundación René Barón; ArgentinaFil: Exeni, Andrea. Hospital Universitario Austral; ArgentinaFil: Santiago, Adriana. Hospital Municipal del Niño de San Justo La Matanza; ArgentinaFil: Exeni, Ramón. Hospital Municipal del Niño de San Justo La Matanza; Argentin

Antibody Response to Shiga Toxins in Argentinean Children with Enteropathic Hemolytic Uremic Syndrome at Acute and Long-Term Follow-Up Periods

Shiga toxin (Stx)-producing Escherichia coli (STEC) infection is associated with a broad spectrum of clinical manifestations that include diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome (HUS). Systemic Stx toxemia is considered to be central to the genesis of HUS. Distinct methods have been used to evaluate anti-Stx response for immunodiagnostic or epidemiological analysis of HUS cases. The development of enzyme-linked immunosorbent assay (ELISA) and western blot (WB) assay to detect the presence of specific antibodies to Stx has introduced important advantages for serodiagnosis of HUS. However, application of these methods for seroepidemiological studies in Argentina has been limited. The aim of this work was to develop an ELISA to detect antibodies against the B subunit of Stx2, and a WB to evaluate antibodies against both subunits of Stx2 and Stx1, in order to analyze the pertinence and effectiveness of these techniques in the Argentinean population. We studied 72 normal healthy children (NHC) and 105 HUS patients of the urban pediatric population from the surrounding area of Buenos Aires city. Using the WB method we detected 67% of plasma from NHC reactive for Stx2, but only 8% for Stx1. These results are in agreement with the broad circulation of Stx2-expressing STEC in Argentina and the endemic behavior of HUS in this country. Moreover, the simultaneous evaluation by the two methods allowed us to differentiate acute HUS patients from NHC with a great specificity and accuracy, in order to confirm the HUS etiology when pathogenic bacteria were not isolated from stools

Adherencia al tratamiento de pacientes con artritis reumatoidea que reciben medicamentos biológicos

Introducción: Al igual que en otras enfermedades crónicas, la adherencia al régimen terapéutico de los pacientes con artritis reumatoidea (AR) es baja (entre 30 y 80%), dependiendo de la definición de adherencia y de la metodología empleada para medirla. En este estudio se propone determinar el nivel de adherencia al tratamiento en pacientes con AR que reciben DMAR biológicas e identificar factores asociados a la falta de cumplimiento a la terapia. Material y métodos: Se realizó un estudio analítico, observacional de corte transversal en donde se incluyeron pacientes consecutivos con AR según criterios de clasificación (ACR’87) que se encontraban recibiendo fármacos biológicos para el tratamiento de su enfermedad en los últimos seis meses y que asistieron a la consulta ambulatoria. Para la valoración de la adherencia a DMAR se utilizaron los cuestionarios CQR (Compliance Questionnaire on Rheumatology) y el cuestionario SMAQ (Simplified Medication Adherence Questionnaire). Resultados: Se encuestaron 345 pacientes. Mediante el cuestionario SMAQ se observó una adherencia del 50% (159 pacientes). El Cuestionario CQR tuvo un puntaje mediano de 78 puntos (RIC 67-86). El 47% (147 pacientes) fueron adherentes (CQR >80). Sobre los pacientes incluidos, 151 (48%) refirieron no haber tenido ningún retraso, pérdida o adelanto de la dosis del biológico en los últimos 6 meses de tratamiento. El 52% no adherentes tuvo como causas: 146 (46%) pérdida de al menos una dosis del biológico con una mediana de dosis perdidas de 2 (RIQ: 1-3); 117 (37%) tuvo al menos un retraso en las dosis del biológico y 8 (2%) delantó la dosis. Los factores asociados al no cumplimiento de la terapia biológica fueron el tipo de cobertura médica, que el paciente no haya notado mejoría y la esperanza de una rápida respuesta al tratamiento, y la falta de adherencia a DMAR

Pathogenic role of inflammatory response during Shiga toxin-associated hemolytic uremic syndrome (HUS)

Hemolytic uremic syndrome (HUS) is defined as a triad of noninmune microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The most frequent presentation is secondary to Shiga toxin (Stx)-producing Escherichia coli (STEC) infections, which is termed postdiarrheal, epidemiologic or Stx-HUS, considering that Stx is the necessary etiological factor. After ingestion, STEC colonize the intestine and produce Stx, which translocates across the intestinal epithelium. Once Stx enters the bloodstream, it interacts with renal endothelial and epithelial cells, and leukocytes. This review summarizes the current evidence about the involvement of inflammatory components as central pathogenic factors that could determine outcome of STEC infections. Intestinal inflammation may favor epithelial leakage and subsequent passage of Stx to the systemic circulation. Vascular damage triggered by Stx promotes not only release of thrombin and increased fibrin concentration but also production of cytokines and chemokines by endothelial cells. Recent evidence from animal models and patients strongly indicate that several immune cells types may participate in HUS physiopathology: neutrophils, through release of proteases and reactive oxygen species (ROS); monocytes/macrophages through secretion of cytokines and chemokines. In addition, high levels of Bb factor and soluble C5b-9 (sC5b-9) in plasma as well as complement factors adhered to platelet-leukocyte complexes, microparticles and microvesicles, suggest activation of the alternative pathway of complement. Thus, acute immune response secondary to STEC infection, the Stx stimulatory effect on different immune cells, and inflammatory stimulus secondary to endothelial damage all together converge to define a strong inflammatory status that worsens Stx toxicity and disease.Fil: Exeni, Ramon Alfonso. Provincia de Buenos Aires. Hospital Municipal del Niño; ArgentinaFil: Fernández Brando, Romina Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Santiago, Adriana Patricia. Provincia de Buenos Aires. Hospital Municipal del Niño; ArgentinaFil: Fiorentino, Gabriela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Provincia de Buenos Aires. Hospital Municipal del Niño; ArgentinaFil: Exeni, Andrea Mariana. Provincia de Buenos Aires. Hospital Austral; ArgentinaFil: Ramos, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Palermo, Marina Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

Association of haemolytic uraemic syndrome with dysregulation of chemokine receptor expression in circulating monocytes

Haemolytic uraemic syndrome (HUS) is the major complication of Escherichia coli gastrointestinal infections that are Shiga toxin (Stx) producing. Monocytes contribute to HUS evolution by producing cytokines that sensitize endothelial cells to Stx action and migration to the injured kidney. As CC chemokine receptors (CCRs) are involved in monocyte recruitment to injured tissue, we analysed the contribution of these receptors to the pathogenesis of HUS. We analysed CCR1, CCR2 and CCR5 expression in peripheral monocytes from HUS patients during the acute period, with healthy children as controls. We observed an increased expression of CCRs per cell in monocytes from HUS patients, accompanied by an increase in the absolute number of monocytes CCR1+, CCR2+ and CCR5+. It is interesting that prospective analysis confirmed that CCR1 expression positively correlated with HUS severity. The evaluation of chemokine levels in plasma showed that regulated on activation of normal T-cell-expressed and -secreted (RANTES) protein was reduced in plasma from patients with severe HUS, and this decrease correlated with thrombocytopenia. Finally, the expression of the higher CCRs was accompanied by a loss of functionality which could be due to a mechanism for desensitization to compensate for altered receptor expression. The increase in CCR expression correlates with HUS severity, suggesting that the dysregulation of these receptors might contribute to an increased risk of renal damage. Activated monocytes could be recruited by chemokines and then receptors could be dysregulated. The dysregulation of CCRs and their ligands observed during the acute period suggests that a chemokine pathway would participate in HUS development.Fil: Ramos, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Ruggieri, Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Panek, Cecilia Analía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Mejias, María Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Fernández Brando, Romina Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Abrey Recalde, Maria Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Exeni, Andrea. Hospital Municipal del Niño; ArgentinaFil: Barilari, Catalina. Municipio de La Matanza. Hospital Municipal del Niño; ArgentinaFil: Exeni, Ramon. Municipio de La Matanza. Hospital Municipal del Niño; ArgentinaFil: Palermo, Marina Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

Frequencies of Stx2 and Stx1 antibodies.

<p>The frequency of reactive plasma samples against Stx1 (<b>A</b>) or Stx2 (<b>B</b>) in age-matched normal healthy children (NHC) (n = 72), in patients with enteropathic HUS at acute period (n = 56), or after recovery (HUSrec) (n = 49) are shown. Each bar represents non-reactive plasma samples (light grey) or samples reacting with only B subunit (black), only A subunit (striped), or with both subunits (A and B) (white) of Stx1/Stx2 assayed by WB analysis. <b>A</b>) Significant differences were not observed between the groups (p = 0.55, Chi-square test). <b>B</b>) ^#p<0.05 vs HUS and HUSrec, Chi-square test; *p<0.05 vs HUS and HUSrec, ** p<0.01 vs NHC, Fisher's exact test.</p

Correlation of anti-Stx2 B IgG ELISA plasma values from HUSrec patients with the time since the enteropathic HUS episode.

<p>OD₄₉₂ values obtained at different times (months) since the HUS episode are individually depicted. The regression line ± 2SD is indicated by the whole and dashed lines, respectively. Correlation coefficient, r = −0.41, p<0.005.</p

Antibodies against Stx2 B subunit measured by ELISA.

<p><b>A</b>) Absorbance values by ELISA assay detecting anti-Stx2 B IgG in plasma from NHC, HUS or HUSrec groups were segregated according the result (positive or negative) obtained by WB for the Stx2 B subunit. OD₄₉₂ values obtained are individually depicted. The horizontal whole line (OD₄₉₂ = 0.226) indicates the cut-off value to consider a plasma sample as positive or negative. <b>B</b>) Relationship between results of anti-Stx2 B antibodies obtained by ELISA and WB assays. Bars represent the frequency of positive plasma against Stx2 B subunit by the two methods (light grey), positive sera by at least one of the methods (white) and negative by the two methods (dark grey) in normal healthy children (NHC), HUS patients at acute period (HUS) or after recovery (HUSrec). *p<0.0005 vs NHC and HUSrec, Chi-square test.</p

Uso de Eculizumab en Síndrome Urémico Hemolítico: una opción terapéutica en el compromiso neurológico severo. Reporte de dos casos

Hemolytic Uremic Syndrome is an endemic disease in Latin America. Argentina is one of the countries where most cases are reported, with a rate of ten cases per 100,000 children under five years old. It is the first cause of acute renal failure (ARF), and responsible for 9% of kidney transplants. This pathology is characterized by a classic triad: microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. The main etiological agent of HUS is the bacterium Shiga toxin-producing Escherichia coli. HUS has an acute mortality lower than 5%.(1-2)There is evidence of the active role of the Shiga toxin in the activation of the complement by binding to factor H. Eculizumab is a monoclonal antibody which inhibits the formation of the membrane attack complex (C5b-9), given its great affinity for C5 of the complement cascade. Its infusion is approved to treat atypical HUS, posing its usefulness to treat severe typical HUS with acute neurological involvement as an alternative to inhibit the complement cascade and stop toxin damage.We present two pediatric patients with SUH diagnosis with shiga toxin rescue; these patients, who showed severe neurological involvement, were treated with Eculizumab and had a favorable response.El síndrome urémico hemolítico típico es una enfermedad endémica en América Latina. Argentina es uno de los países con más casos reportados, con una tasa de diez casos cada 100.000 menores de cinco años. Es la primera causa de insuficiencia renal aguda, y responsable del 9% de los trasplantes renales. Esta patología se caracteriza por una tríada clásica: anemia microangiopática, trombocitopenia e insuficiencia renal aguda. El principal agente etiológico del Síndrome Urémico Hemolítico es la bacteria Escherichia coli, productora de la toxina Shiga. El Síndrome Urémico Hemolítico tiene una mortalidad aguda inferior al 5%.(1-2)Existe evidencia acerca del rol activo de la shiga toxina en la activación del complemento a través de su unión al factor H. El eculizumab es un anticuerpo monoclonal que inhibe la formación del complejo de ataque de membrana (C5b-9), por su alta afinidad a C5 de la cascada del complemento. Su infusión está aprobada para el tratamiento del Síndrome Urémico Hemolítico atípico, planteándose su utilidad en casos de Síndrome Urémico Hemolítico típico grave con compromiso neurológico severo como alternativa para inhibir la cascada de complemento, y así detener el daño producido por la toxina.Se presentan dos casos de pacientes pediátricos con diagnóstico Síndrome Urémico Hemolítico con rescate de Shiga toxina, con compromiso neurológico grave y que recibieron tratamiento con eculizumab con respuesta favorable