Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli in a renal transplant recipient case report / Síndrome hemolítico-urêmica causada por Escherichia coli produtora de toxina Shiga em um relato de caso de receptor de transplante renal

Abstract Thrombotic microangiopathies are disorders characterized by nonimmune microangiopathic hemolytic anemia, thrombocytopenia, and multi-systemic failure. They are classified as thrombotic thrombocytopenic purpura, atypical hemolytic-uremic syndrome, and typical hemolytic uremic syndrome. The latter is associated with intestinal infections by Shiga toxin-producing bacteria. Typical hemolytic uremic syndrome in adults is an extremely rare condition, characterized by high morbidity and mortality. It has been seldom described in solid organ transplant recipients. Here is presented the case of a kidney transplant recipient who had typical hemolytic uremic syndrome with multisystem commitment, refractory to management and with a fatal outcome.

Resumo Microangiopatias trombóticas são distúrbios caracterizados por anemia hemolítica microangiopática não imune, trombocitopenia e insuficiência multissistêmica. Elas são classificadas como púrpura trombocitopênica trombótica, síndrome hemolítico-urêmica atípica e síndrome urêmica hemolítica típica. Essa última está associada a infecções intestinais por bactérias produtoras da toxina Shiga. A síndrome hemolítica urêmica típica em adultos é uma condição extremamente rara, caracterizada por alta morbimortalidade. Esta é raramente descrita em receptores de transplantes de órgãos sólidos. Apresentamos aqui o caso de um receptor de transplante renal que apresentava síndrome hemolítico-urêmica típica com comprometimento multissistêmico, refratário ao tratamento, e com desfecho fatal.

Síndrome hemolítico urémico asociado a toxina Shiga con hipocomplementemia en edad atípica. Caso clínico

The Shiga toxin associated (Stx) hemolytic uremic syndrome (HUS) is an important cause of acute renal failure (ARF) and the most common cause of thrombotic microangiopathy (TMA) in pediatrics. Primary atypical HUS (aHUS) is a rare disease due to a genetic defect in the alternative complement pathway. Both diseases may share clinical and laboratory elements, making differential diagnosis difficult, such as the presence of diarrhea in aHUS or complement alterations in HUS-Stx. The treatment and prognosis of both diseases is completely different. We report a 15-year-old male with severe HUS. After a self-limited diarrheal syndrome, he had a severe TMA and ARF, requiring renal replacement therapy. An extensive etiological study was carried out, ruling out the main causes of TMA. Alterations in complement factors were observed. Finally, the diagnosis of HUS-Stx was established. The patient evolved favorably with recovery of renal function.

Consensus regarding diagnosis and management of atypical hemolytic uremic syndrome.

Thrombotic microangiopathy (TMA) is defined by specific clinical characteristics, including microangiopathic hemolytic anemia, thrombocytopenia, and pathologic evidence of endothelial cell damage, as well as the resulting ischemic end-organ injuries. A variety of clinical scenarios have features of TMA, including infection, pregnancy, malignancy, autoimmune disease, and medications. These overlapping manifestations hamper differential diagnosis of the underlying pathogenesis, despite recent advances in understanding the mechanisms of several types of TMA syndrome. Atypical hemolytic uremic syndrome (aHUS) is caused by a genetic or acquired defect in regulation of the alternative complement pathway. It is important to consider the possibility of aHUS in all patients who exhibit TMA with triggering conditions because of the incomplete genetic penetrance of aHUS. Therapeutic strategies for aHUS are based on functional restoration of the complement system. Eculizumab, a monoclonal antibody against the terminal complement component 5 inhibitor, yields good outcomes that include prevention of organ damage and premature death. However, there remain unresolved challenges in terms of treatment duration, cost, and infectious complications. A consensus regarding diagnosis and management of TMA syndrome would enhance understanding of the disease and enable treatment decision-making.

Role of alternative complement pathway overactivation in malignant nephrosclerosis / 中华肾脏病杂志

Objective@#To study the role of alternative complement pathway overactivation in malignant nephrosclerosis.@*Methods@#(1) Fifty patients with confirmed malignant nephrosclerosis by renal needle biopsy were enrolled. Meanwhile, twenty-five cases of time-zero renal needle biopsy were enrolled as control subjects. Enzyme linked immunosorbent assay (ELISA) was used to detect alternative complement pathway of the complement initiation factor B, positive regulation factor P, negative regulation factor H, and the complement end products C3a and C5a in the plasma and urine. (2) Immunohistochemistry was used to detect the deposition of the complement end product C5b-9, C4d and mannan binding lectin (MBL) of lectin pathway in the renal biopsies. Double immunofluorescence labeling method was used to assay the deposition of C5b-9 and CD34 (endothelial cell marker) in the arteriolar endothelium and glomerular capillary endothelium.@*Results@#(1) The plasma and urine levels of complement factor B, factor P, C3a and C5a in malignant nephrosclerosis patients were significantly higher than those in control subjects (all P<0.05), while the plasma and urine levels of complement factor H in malignant nephrosclerosis patients were lower than those in control subjects (all P<0.05). (2) The plasma level of factor P was positively correlated with 24 h urine protein (rs=0.465, P=0.001). Urinary factor B/urinary creatinine, urinary factor P/urinary creatinine and urinary C3a/urinary creatinine were positively correlated with serum creatinine in malignant nephrosclerosis patients (rs=0.483, P<0.001; rs=0.352, P=0.012; rs=0.319, P=0.024), while urinary factor H/urinary creatinine was negatively correlated with serum creatinine and 24 h urine protein (rs=-0.299, P=0.035; rs=-0.342, P=0.015). Urinary C5a/urinary creatinine was positively correlated with serum creatinine and 24 h urine protein (rs=0.525, P<0.001; rs=0.496, P<0.001). (3) Immunohistochemical results showed that there were C5b-9 deposited in the arterioles and glomerular capillary wall in malignant nephrosclerosis patients, and no deposition in control renal tissues. Meanwhile, the semi-quantitative scores showed that C5b-9 deposition intensity was positively correlated with serum creatinine and 24 h urine protein (rs=0.791, P<0.001; rs=0.345, P=0.014). The double immunofluorescence labeling analysis showed that the C5b-9 and CD34 deposited in the arteriolar endothelium and glomerular capillary endothelium. (4) Plasma level of factor B in malignant nephrosclerosis patients was positively correlated with plasma C3a level (r=0.331, P=0.022). Plasma level of factor P was positively correlated with C5b-9 score (rs=0.300, P=0.034). Urinary B was positively correlated with urinary C3a, C5a and C5b-9 score (rs=0.311, P=0.028; rs=0.465, P=0.001; rs=0.428, P=0.002). Urinary factor P was also positively correlated with urinary C3a and C5a (rs=0.307, P=0.030; rs=0.442, P=0.001). Immunohistochemical result showed that there were C4d deposited in the arterioles and glomerular, and no deposition of MBL.@*Conclusion@#Complement activation via the alternative pathway may be involved in malignant nephrosclerosis and related to the severity of the disease.

Role of alternative complement pathway overactivation in malignant nephrosclerosis / 中华肾脏病杂志

Objective To study the role of alternative complement pathway overactivation in malignant nephrosclerosis.Methods (1) Fifty patients with confirmed malignant nephrosclerosis by renal needle biopsy were enrolled.Meanwhile,twenty-five cases of time-zero renal needle biopsy were enrolled as control subjects.Enzyme linked immunosorbent assay (ELISA) was used to detect alternative complement pathway of the complement initiation factor B,positive regulation factor P,negative regulation factor H,and the complement end products C3a and C5a in the plasma and urine.(2) Immunohistochemistry was used to detect the deposition of the complement end product C5b-9,C4d and mannan binding lectin (MBL) of lectin pathway in the renal biopsies.Double immunofluorescence labeling method was used to assay the deposition of C5b-9 and CD34 (endothelial cell marker) in the arteriolar endothelium and glomerular capillary endothelium.Results (1) The plasma and urine levels of complement factor B,factor P,C3a and C5a in malignant nephrosclerosis patients were significantly higher than those in control subjects (all P ＜ 0.05),while the plasma and urine levels of complement factor H in malignant nephrosclerosis patients were lower than those in control subjects (all P ＜ 0.05).(2) The plasma level of factor P was positively correlated with 24 h urine protein (rs=0.465,P=0.001).Urinary factor B/urinary creatinine,urinary factor P/urinary creatinine and urinary C3a/urinary creatinine were positively correlated with serum creatinine in malignant nephrosclerosis patients (rs=0.483,P ＜ 0.001;rs=0.352,P=0.012;rs=0.319,P=0.024),while urinary factor H/urinary creatinine was negatively correlated with serum creatinine and 24 h urine protein (rs=-0.299,P=0.035;rs=-0.342,P=0.015).Urinary C5a/urinary creatinine was positively correlated with serum creatinine and 24 h urine protein (rs=0.525,P ＜ 0.001;rs=0.496,P ＜ 0.001).(3) Immunohistochemical results showed that there were C5b-9 deposited in the arterioles and glomerular capillary wall in malignant nephrosclerosis patients,and no deposition in control renal tissues.Meanwhile,the semi-quantitative scores showed that C5b-9 deposition intensity was positively correlated with serum creatinine and 24 h urine protein (rs=0.791,P＜ 0.001;rs=0.345,P=0.014).The double immunofluorescence labeling analysis showed that the C5b-9 and CD34 deposited in the arteriolar endothelium and glomerular capillary endothelium.(4) Plasma level of factor B in malignant nephrosclerosis patients was positively correlated with plasma C3a level (r=0.331,P=0.022).Plasma level of factor P was positively correlated with C5b-9 score (rs=0.300,P=0.034).Urinary B was positively correlated with urinary C3a,C5a and C5b-9 score (rs=0.311,P=0.028;rs=0.465,P=0.001;rs=0.428,P=0.002).Urinary factor P was also positively correlated with urinary C3a and C5a (rs=0.307,P=0.030;rs=0.442,P=0.001).Immunohistochemical result showed that there were C4d deposited in the arterioles and glomerular,and no deposition of MBL.Conclusion Complement activation via the alternative pathway may be involved in malignant nephrosclerosis and related to the severity of the disease.

The role of complement system in thrombotic microangiopathy and its research progress / 中华检验医学杂志

Thrombotic microangiopathy (TMA) is a group of acute clinical pathological syndromes with common pathological features, which include hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura syndrome. They have many similarities in etiology and clinical presentation. The role of abnormal activation of complement bypass pathway in the genesis and development of HUS has been recognized. More than 100 kinds of complement regulatory factors or gene mutations of complement itself were found to be associated with the development of HUS, which resulted in the decrease of negative complement regulatory protein activity or the increase of complement activation protein function. Abnormal activation of complement system resulted in endothelial injury and thrombosis. Loss of ADAMTS13 activity (<10%) is the most important pathogenesis of TTP. However, there are more and more evidence that complement bypassing pathway is over-regulated and over-activated in the formation of TTP. At present, the research of TMA is focused on finding specific complement-activated biomarkers in patients with various forms of TMA and developing new targeted therapeutic drugs for the disease.

The role of complement system in thrombotic microangiopathy and its research progress / 中华检验医学杂志

Thrombotic microangiopathy (TMA) is a group of acute clinical pathological syndromes with common pathological features, which include hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura syndrome. They have many similarities in etiology and clinical presentation. The role of abnormal activation of complement bypass pathway in the genesis and development of HUS has been recognized. More than 100 kinds of complement regulatory factors or gene mutations of complement itself were found to be associated with the development of HUS, which resulted in the decrease of negative complement regulatory protein activity or the increase of complement activation protein function . Abnormal activation of complement system resulted in endothelial injury and thrombosis. Loss of ADAMTS13 activity (<10％) is the most important pathogenesis of TTP. However, there are more and more evidence that complement bypassing pathway is over-regulated and over-activated in the formation of TTP. At present, the research of TMA is focused on finding specific complement-activated biomarkers in patients with various forms of TMA and developing new targeted therapeutic drugs for the disease.

Síndrome hemolítico urémico atípico: papel del perfil genético / Atypical hemolytic uremic syndrome: role of the genetic profile

Resumen: El síndrome hemolítico urémico es una microangiopatía trombótica caracterizada por anemia hemolítica microangiopática, trombocitopenia y daño renal agudo. El síndrome hemolítico urémico típico (el más común) es ocasionado por bacterias productoras de la toxina Shiga, típicamente por cepas de Escherichia coli. El término síndrome hemolítico urémico atípico se usa para referirse a los pacientes que padecen este cuadro por causas diferentes. Las manifestaciones clínicas y paraclínicas no son suficientes para diferenciar el síndrome hemolítico urémico atípico de otras microangiopatías trombóticas, por lo que la determinación de la actividad de ADAMTS13 y la prueba de la toxina Shiga resultan esenciales para establecer el diagnóstico preciso. Aunque en la actualidad el diagnóstico definitivo requiere confirmación genética, las pruebas genéticas son costosas y poco útiles para el diagnóstico inicial; sin embargo, más que importancia diagnóstica, tiene gran valor pronóstico, permite prescribir el tratamiento adecuado disminuyendo significativamente la morbilidad y mortalidad atribuibles a esta enfermedad.

Abstract: The haemolytic uraemic syndrome is a thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute renal injury. The typical haemolytic uraemic syndrome (tHUS, the most common) is caused by bacteria that produce Shiga toxin, typically strains of Escherichia coli. On the other hand, the term atypical haemolytic uraemic syndrome (aHUS) is used to refer to those patients who develop this condition due to different etiologies. The clinical and paraclinical manifestations are not enough to differentiate the aHUS from other thrombotic microangiopathies, so the determination of the activity of ADAMTS13 and the Shiga toxin test are essential to establish the precise diagnosis. Although currently the diagnosis requires genetic confirmation, the genetic tests are expensive and not very useful for the initial diagnosis; however, more than diagnostic importance, it has a great prognostic value allowing establishing an adequate management and significantly reducing the morbidity and mortality attributable to this condition.

Hemolytic Uremic Syndrome in Pregnancy and Postpartum.

BACKGROUND: Pregnancy is associated with various forms of thrombotic microangiopathy, including hemolytic uremic syndrome. A previous small French study suggested that pregnancy-associated hemolytic uremic syndrome was to be included in the spectrum of atypical hemolytic uremic syndrome linked to complement alternative pathway dysregulation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We sought to retrospectively analyze the presentation, outcome, and frequency of complement alternative pathway gene variants in a larger international (France, United Kingdom, Italy) cohort of patients with pregnancy-associated hemolytic uremic syndrome. RESULTS: Eighty-seven patients with pregnancy-associated hemolytic uremic syndrome were included. Hemolytic uremic syndrome occurred mainly during the first pregnancy (58%) and in the postpartum period (76%). At diagnosis, 56 (71%) patients required dialysis. Fifty-six (78%) patients underwent plasma exchanges, 21 (41%) received plasma infusions, and four (5%) received eculizumab. During follow-up (mean duration of 7.2 years), 41 (53%) patients reached ESRD, 15 (19%) had CKD, and 18 (28%) patients experienced hemolytic uremic syndrome relapse. Twenty-four patients (27%) received a kidney transplant and a recurrence of hemolytic uremic syndrome occurred in 13 (54%) patients. Variants in complement genes were detected in 49 (56%) patients, mainly in the CFH (30%) and CFI genes (9%). CONCLUSIONS: Pregnancy-associated hemolytic uremic syndrome and atypical hemolytic uremic syndrome nonrelated to pregnancy have the same severity at onset and during follow-up and the same frequency of complement gene variants.

Indications of underdiagnosis of atypical haemolytic uraemic syndrome in a cohort referred to the Coagulation Unit in Malmo, Sweden, for analysis of ADAMTS13 2007-2012.

AIM: Complement-mediated atypical haemolytic uraemic syndrome (aHUS) is a rare disease with high mortality and morbidity if left untreated. The diagnostic work-up is complicated and the manifestations overlap with other conditions. Therefore, we hypothesize that complement-mediated aHUS is an under diagnosed disease. METHODS: A cohort of 768 referrals referred to the Coagulation Unit in Malmo, Sweden, for analysis of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), 2007-2012, were retrospectively reviewed. Subjects were included on the basis of presence of haemolytic anaemia, thrombocytopaenia, renal failure and ADAMTS13 > 0.05. They were excluded if tested positive for Escherichia coli. Included subjects were categorized as "suspected HUS" with and without potential causes and triggers. Levels of C3 and C4, presence of complement factor H (CFH)-specific antibodies and associated deficiency in complement factor H related protein 1 (CFHR1) were analyzed on frozen samples. RESULTS: In total, 134/316 (42%) unique subjects fulfilled inclusion criteria; 103 were categorized as "suspected HUS associated with potential causes/triggers" and 31 subjects categorized as "suspected HUS" without such association. One case of complement-mediated aHUS had been confirmed during the treatment period. Laboratory analyses performed showed that in total 78 cases had findings consistent with complement-mediated aHUS: 24 cases indicated presence of CFH-specific antibodies whereof five cases had isolated low C3 titres and six cases had deficiency of CFHR1. Additionally 54 cases indicated isolated alternative pathway consumption. CONCLUSION: The results suggest that the presence of complement-mediated aHUS was under diagnosed in this cohort calling for improvement of diagnostic availability.

Alteraciones del sistema complemento en pacientes con anemia drepanocítica en estado basal / Alterations of the complement system in patients with basal sickle cell anemia

Se determinó la actividad de las vías clásica y alternativa del complemento, así como la cuantificación de algunos de sus componentes en 46 pacientes con anemia drepanocítica (AD) (hemoglobina SS), 21 sin complicaciones clínicas y 25 con estas; entre las más frecuentes encontramos: número de infecciones, úlceras maleolares, crisis vasooclusivas, hepáticas y aplásticas, considerando como límite un año anterior a la toma de muestra de sangre. Se demostró una disminución significativa de la actividad de la vía alternativa, factor B y del componente C3 en el grupo de pacientes con complicaciones clínicas. Se observó una correlación significativa entre el número de crisis vasooclusivas e infecciones y la actividad de la vía alternativa, el factor B y el C3. Estos resultados sugieren que los fenómenos inflamatorios que pueden persistir en pacientes con AD en estado basal, fundamentalmente aquellos con historia anterior de complicaciones clínicas, pueden provocar alteraciones en la actividad del complemento.

The activity of the classic and alternative complement pathways, as well as the quantitation of some of their components was determined in 46 patients with sickle cell anemia (haemoglobin SS), 21 with no clinical complications and 25 with them. Among the most frequent complications we found: number of infections, malleolar ulcers, and vaso-occlusive, hepatic and aplastic crises. A year previous to the blood sample taking was considered as the limit. A significant reduction of the activity of the alternative pathway, factor B and component C3 was proved in the group of patients with clinical complications. A marked correlation was observed between the number of vaso-occlusive crises and infections and the activity of the alternative pathway, factor B and complement C3. These results suggest that the inflammatory phenomena that may persist among patients with basal sickle cell anemia, mainly those with prior history of clinical complications, may produce alterations in the complement activity.