Near-fatal cocaine intoxication in an infant with thrombotic microangiopathy associated with multiple organ failure / Intoxicação grave por cocaína em criança com microangiopatia trombótica associada à falência múltipla de órgãos

ABSTRACT Objective: To report a pediatric case of drug-induced thrombotic microangiopathy caused by cocaine Case description: We report a nine-month-old patient who developed thrombotic microangiopathies after extreme cocaine intoxication, multiple organ dysfunction syndrome with hemodynamic dysfunction, anuric renal failure, liver failure, encephalopathy, and myocardial injury, corresponding phenotypically to thrombocytopenia-associated multiple organ failure. The patient received continuous venous hemofiltration and therapeutic plasma exchange, recovering satisfactorily. She was discharged after 30 days of hospitalization under the guidance of the childcare service, and was healthy after one year of follow-up. Toxicological samples confirmed high levels of cocaine and derivatives in blood, urine and hair. Comments: To our knowledge, this is the first reported pediatric case. There are particularities of cocaine intoxication pathophysiology that can trigger thrombotic microangiopathies because of vasoconstriction, direct endothelial injury, platelet activation, and increasing von Willebrand factor and fibrinogen levels. All of which results in a prothrombotic state, inflammatory dysregulation, and microvascular thrombi. The increasing use of cocaine, especially among young adults, puts children at high risk of toxicity, either by passive unintentional exposure, or abuse due to the increased availability in homes.

RESUMO Objetivo: Relatar um caso pediátrico de microangiopatia trombótica induzida por drogas causada por cocaína Descrição do caso: Relatamos uma paciente de nove meses de idade que desenvolveu microangiopatia trombótica após intoxicação extrema por cocaína, síndrome de disfunção de múltiplos órgãos com disfunção hemodinâmica, insuficiência renal anúrica, insuficiência hepática, encefalopatia e lesão miocárdica, correspondendo fenotipicamente à falência múltipla de órgãos associada à trombocitopenia. A paciente recebeu hemofiltração venosa contínua e plasmaférese terapêutica, recuperando-se satisfatoriamente. Recebeu alta após 30 dias de internação sob orientação do serviço de puericultura e estava saudável após um ano de seguimento. Amostras toxicológicas confirmaram altos níveis de cocaína e derivados no sangue, urina e cabelos. Comentários: Até onde sabemos, este é o primeiro caso pediátrico relatado. Existem particularidades da fisiopatologia da intoxicação por cocaína que podem desencadear a microangiopatia trombótica devido à vasoconstrição, lesão endotelial direta, ativação plaquetária e aumento do fator de von Willebrand e dos níveis de fibrinogênio. Tudo isso resulta em um estado pró-trombótico, desregulação inflamatória e trombos microvasculares. O uso crescente de cocaína, principalmente entre adultos jovens, coloca as crianças em alto risco de toxicidade, seja por exposição passiva não intencional ou abuso devido à maior disponibilidade nas residências.

Púrpura trombótica trombocitopénica en pediatría. Reporte de un caso / Thrombotic thrombocytopenic purpura in pediatrics. A case report

La púrpura trombótica trombocitopénica es una entidad poco frecuente en pediatría, pero de alta mortalidad sin tratamiento adecuado y oportuno. Se caracteriza por presentar anemia hemolítica microangiopática asociada a signos y síntomas neurológicos, cardíacos, abdominales y menos frecuentemente renales; puede estar acompañada de fiebre. En niños, el diagnóstico se basa en los hallazgos clínicos y de laboratorio. La actividad de ADAMTS13 <10 % apoya, pero no confirma el diagnóstico y, dada la gravedad de la patología, el resultado no debe retrasar el inicio del tratamiento. Se presenta una paciente de 15 años, previamente sana, con signos neurológicos asociados a anemia hemolítica y trombocitopenia. Durante su internación, se arribó al diagnóstico de púrpura trombótica trombocitopénica adquirida.

Thrombotic thrombocytopenic purpura is a rare disease in pediatrics, but it has a high mortality if not managed in an adequate and timely manner. It is characterized by microangiopathic hemolytic anemia associated with neurological, cardiac, abdominal, and less frequently, renal signs and symptoms; it may be accompanied by fever. In children, diagnosis is based on clinical and laboratory findings. ADAMTS13 activity < 10% supports the diagnosis but does not confirm it and, given its severity, the result should not delay treatment initiation. Here we describe the case of a previously healthy 15-year-old female patient with neurological signs associated with hemolytic anemia and thrombocytopenia. During hospitalization, she was diagnosed with acquired thrombotic thrombocytopenic purpura.

Hemolytic-uremic syndrome: 24 years' experience of a pediatric nephrology unit / Síndrome hemolítico-urêmica: 24 anos de experiência de uma unidade de nefrologia pediátrica

Abstract Introduction: A better understanding of hemolytic-uremic syndrome (HUS) pathophysiology significantly changed its treatment and prognosis. The aim of this study is to characterize the clinical features, severity, management, and outcomes of HUS patients. Materials and Methods: Retrospective study of HUS patients admitted to a Pediatric Nephrology Unit between 1996 and 2020. Demographic and clinical data regarding etiology, severity, treatment strategies, and patient outcome were collected. Results: Twenty-nine patients with HUS were admitted to our unit, but four were excluded. Median age at diagnosis was two years (2 months - 17 years). Clinical manifestations included diarrhea, vomiting, oliguria, hypertension, and fever. During the acute phase, 14 patients (56%) required renal replacement therapy. Infectious etiology was identified in seven patients (five Escherichia coli and two Streptococcus pneumoniae). Since 2015, 2/7 patients were diagnosed with complement pathway dysregulation HUS and there were no cases of infectious etiology detected. Six of these patients received eculizumab. The global median follow-up was 6.5 years [3 months-19.8 years]. One patient died, seven had chronic kidney disease, four of whom underwent kidney transplantation, one relapsed, and seven had no sequelae. Conclusion: These results reflect the lack of infectious outbreaks in Portugal and the improvement on etiological identification since genetic testing was introduced. The majority of patients developed sequels and mortality was similar to that of other countries. HUS patients should be managed in centers with intensive care and pediatric nephrology with capacity for diagnosis, etiological investigation, and adequate treatment. Long-term follow-up is essential.

Resumo Introdução: Um melhor entendimento da fisiopatologia da síndrome hemolítico-urêmica (SHU) mudou significativamente seu tratamento e prognóstico. Este estudo teve como objetivo caracterizar condições clínicas, gravidade, manejo e desfechos de pacientes com SHU. Materiais e Métodos: Estudo retrospectivo de pacientes com SHU admitidos numa Unidade de Nefrologia Pediátrica entre 1996-2020. Foram coletados dados demográficos e clínicos sobre etiologia, gravidade, estratégias de tratamento, desfechos de pacientes. Resultados: 29 pacientes com SHU foram admitidos em nossa unidade, mas quatro foram excluídos. A idade mediana ao diagnóstico foi dois anos (2 meses-17 anos). Manifestações clínicas incluíram diarreia, vômitos, oligúria, hipertensão e febre. Durante a fase aguda, 14 pacientes (56%) necessitaram de terapia renal substitutiva. Identificou-se a etiologia infecciosa em sete pacientes (cinco Escherichia coli; dois Streptococcus pneumoniae). Desde 2015, 2/7 pacientes foram diagnosticados com SHU por desregulação da via do complemento e não foram detectados casos de etiologia infecciosa. Seis desses pacientes receberam eculizumab. A mediana global de acompanhamento foi 6,5 anos [3 meses-19,8 anos]. Um paciente faleceu, sete apresentaram doença renal crônica, sendo quatro submetidos a transplante renal, uma recidiva e sete sem sequelas. Conclusão: Estes resultados refletem a ausência de surtos infecciosos em Portugal e a melhoria na identificação etiológica desde que os testes genéticos foram introduzidos. A maioria dos pacientes desenvolveu sequelas e a mortalidade foi semelhante à de outros países. Pacientes com SHU devem ser manejados em centros com cuidados intensivos e nefrologia pediátrica com capacidade para diagnóstico, investigação etiológica e tratamento adequado. O acompanhamento alongo prazo é essencial.

Renal thrombotic microangiopathy induced by targeted therapy combined with immunotherapy: a case report / 中华肾脏病杂志

Targeted therapy and immunotherapy have achieved great success in treating various solid and non-solid tumors, but the incidence of drugs-related adverse events is relatively high. The paper reports a case of renal thrombotic microangiopathy in an intrahepatic cholangiocarcinoma patient who underwent targeted therapy combined with immunotherapy. During the treatment, the tumor burden relieved continuously, but the patient developed proteinuria, edema and hypertension. The ADAMTS13 activity and inhibitors were normal, while the antiphospholipid antibody was positive. The patient was finally diagnosed as glomerular thrombotic microangiopathy with immune complex deposition by renal biopsy. After the cease of the antineoplastic agents and treatment with "cordyceps preparations" and "α-keto acids", the patient's blood pressure dropped to normal, her urine protein turnned to weakly positive, and her renal function remained stable.

The paradox of thrombotic thrombocytopenic purpura and the TACO challenge!

Thrombotic thrombocytopenic purpura (TTP) is a rare medical emergency characterized by the pentad of microangiopathic hemolytic anemia, thrombocytopenia, fever, renal failure, and neurological dysfunction. TTP is an infrequent condition and is a thrombotic microangiopathy. TTP is essentially a clinical diagnosis. As untreated TTP has a high mortality, diagnosis is usually presumptive and prompt treatment with plasma exchange is highly beneficial and reduces mortality significantly. Therapeutic plasma exchange with fresh frozen plasma is the standard treatment of choice for TTP. Transfusion-associated reactions may occur in some patients further complicating the disease picture and prolonging hospital stay and recovery. Transfusion-associated circulatory overload and transfusion-associated acute lung injury are the leading cause of transfusion-related mortality. We present here the diagnostic and therapeutic challenges that we faced with a young male patient who presented with fever, jaundice, and seizures.

Anuria, Sudden Blindless, Confusion: A Case of Unusual "Adult Still Disease" / 罕见病研究

A young female patient presented with fever, arthralgia, and rash was diagnosed with adults still's disease. When treated with glucocorticoid steroid, the above patient progressed to anuria, sudden, and confusion. After a teamwork involving different departments, the patient was finally diagnosed with atypical hemolytic uremic syndrome (aHUS) and treated with good outcome. aHUS is a rare disease, while Eculizumab is an orphan drug. The diagnosis and treatment of the patient reveals the importance of multidisciplinary team on the diagnosis and treatment of rare and difficult diseases.

A systemic lupus erythematosus patient with sudden dyspnea and disordered consciousness / 中华风湿病学杂志

Objective:To improve the ability of identification and differential diagnosis of severe systemic lupus erythematosus (SLE).Methods:A severe SLE patient with lupus myocarditis, neuropsychiatric lupus, thrombotic microangiopathy (TMA) and other multiple system involvement was reported and discussed.Results:A young female patient developed albuminuria 5 months ago, edema of both lower limbs 3 months ago, change of consciousness 1 month ago and two convulsions attack 2 days ago. She experienced life threatening manifestations such as neuropsychiatric lupus, myocardial involvement of lupus, and TMA. During the course, her condition was generally improved after glucocorticoid pulse therapy and plasma exchange.Conclusion:Various complicated clinical manifestations related to SLE need to be recognized earlier and intervened as soon as possible.

Clinical study of lupus nephritis complicated with renal thrombotic microangiopathy / 中华肾脏病杂志

Objective:To study the clinicopathological characteristics, treatment and prognosis in lupus nephritis (LN) patients with renal thrombotic microangiopathy (TMA), so as to provide more theoretical basis for clinicians to recognize and treat this disease.Methods:The clinical data of LN patients who underwent renal biopsy in the First Affiliated Hospital of Zhengzhou University from January 1, 2012 to May 31, 2019 were retrospectively collected and analyzed. According to renal clinicopathological examination, the patients were divided into renal TMA group and non-renal TMA group. The clinical data, laboratory examination, renal pathological examination, therapeutic measures and prognostic between the two groups were compared. Follow-up end points were defined as composite ends, including all-cause death, entry into end-stage renal disease, and estimated glomerular filtration rate decrease>50% of baseline. Kaplan-Meier survival curve and log-rank test were used to compare the difference of survival rate between the two groups, and multivariate Cox regression equation was used to analyze the risk factors of endpoint events in LN patients.Results:A total of 1 133 patients with LN were enrolled in this study. Patients with renal TMA were more likely to have hypertension ( χ2=16.310, P<0.001), higher baseline serum creatinine ( Z=-6.918, P<0.001) and 24-hour urine protein ( Z=-2.232, P=0.026), and higher renal pathology activity index (AI) score ( Z=1.957, P=0.001)and chronic index (CI) score ( Z=1.836, P=0.002). The proportions of hormone shock ( P<0.001) and plasma exchange ( P<0.001) in the renal TMA group were higher than those in non-renal TMA group. After treatment of (12±2) months, patients in the renal TMA group had a lower complete response rate ( χ2=10.455, P=0.001) and a higher non-response rate ( χ2=6.047, P=0.014) than those in non-renal TMA group, and were associated with worse prognosis (Log-rank test χ2=26.490, P<0.001). Renal TMA was an independent risk factor for poor prognosis ( HR=2.347, 95% CI 1.210-4.553, P=0.012). Conclusions:Compared with LN patients without renal TMA, LN patients with renal TMA are more likely to have hypertension, with higher serum creatinine, 24-hour urinary protein, AI and CI, suggesting poorer treatment response and renal prognosis. Moreover, renal TMA is an independent risk factor for poor prognosis in patients with LN.

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.

Genetic atypical hemolytic uremic syndrome in children: a 20-year experience from a tertiary center / Síndrome hemolítica urêmica atípica genética em crianças: uma experiência de 20 anos a partir de um centro terciário

Abstract Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, which primarily affects preschool-aged children. This study's aim was to describe the clinical profile, management, and long-term outcome of the genetic aHUS patients admitted to a tertiary care pediatric nephrology center during 20 years. Methods: We performed a retrospective analysis of the clinical records of all aHUS patients younger than 18 years with identified genetic mutations. Data on clinical features, genetic study, therapeutic interventions, and long-term outcomes were reviewed. Results: Five cases of aHUS with an identified genetic mutation were included; all were inaugural cases with the youngest being 4 months old. Complement factor H gene mutation was identified in four patients. Therapeutic plasma exchange was performed for acute management in 4 patients, one of whom also needed acute renal replacement therapy (peritoneal dialysis). All patients went on complete remission, 2 had more than one relapse but only 1 of these progressed to chronic kidney disease during the follow-up period (median (25th-75th percentile), 136 (43.5-200.5) months). Conclusion: In children, the prognosis of renal function seems to be strongly dependent on the genetic background, thus being crucial to perform genetic study in all aHUS cases. In our cohort, 2 patients presented genetic mutations not previously described. Recent innovations on the genetic field leading to the identification of new mutations has lead to a better understanding of aHUS pathogenesis, but further studies, focusing on the genotype-phenotype correlation, with longer follow-up periods, are needed.

Resumo Introdução: A síndrome hemolítica urêmica atípica (SHUa) é um distúrbio raro caracterizado pela tríade de anemia hemolítica microangiopática, trombocitopenia e lesão renal aguda, afetando principalmente crianças em idade pré-escolar. O objetivo deste estudo foi descrever perfil clínico, manejo e desfecho em longo prazo dos pacientes com SHUa genética admitidos em um centro terciário de nefrologia pediátrica durante 20 anos. Métodos: Realizamos análise retrospectiva dos registros clínicos de todos os pacientes com SHUa menores de 18 anos com mutações genéticas identificadas. Revisaram-se dados sobre características clínicas, estudo genético, intervenções terapêuticas e desfechos em longo prazo. Resultados: Incluíram-se cinco casos de SHUa com uma mutação genética identificada; sendo todos casos inaugurais, o mais jovem tendo 4 meses de idade. A mutação no gene do fator H do complemento foi identificada em quatro pacientes. Plasmaférese terapêutica foi realizada para tratamento agudo em 4 pacientes, um dos quais também necessitou terapia renal substitutiva aguda (diálise peritoneal). Todos os pacientes tiveram remissão completa, 2 mais de uma recidiva, mas apenas 1 evoluiu para doença renal crônica durante acompanhamento (mediana (percentil 25°-75°), 136 (43,5-200,5) meses). Conclusão: Em crianças, o prognóstico da função renal parece ser fortemente dependente do histórico genético, sendo crucial realizar estudo genético em todos os casos de SHUa. Em nossa coorte, 2 pacientes apresentaram mutações genéticas não descritas anteriormente. Inovações recentes no campo genético que levaram à identificação de novas mutações conduziram a um melhor entendimento da patogênese SHUa, mas são necessários mais estudos, focando na correlação genótipo-fenótipo, com períodos de acompanhamento mais longos.

Pseudomicroangiopatía trombótica por deficiencia de vitamina B12 en un lactante / Pseudo-thrombotic microangiopathy due to vitamin B12 deficiency in an infant

La seudomicroangiopatía trombótica o síndrome de Moschcowitz es una manifestación infrecuente del déficit de vitamina B12. Se caracteriza por anemia hemolítica con características microangiopáticas, reticulocitos e índices hematimétricos normales o con ligera megaloblastosis, asociados a manifestaciones neurológicas. La vitamina B12 está presente en alimentos proteicos de origen animal. La lactancia materna es una fuente adecuada para los niños cuando los niveles maternos son normales. Se presenta a una paciente de 16 meses que se internó por anemia hemolítica con requerimiento transfusional, plaquetopenia, mal progreso pondoestatural y retraso neuromadurativo. Durante su internación se arribó al diagnóstico de seudomicroangiopatía trombótica secundaria a déficit de vitamina B12.

Pseudo-thrombotic microangiopathy, or Moschcowitz syndrome, is a rare manifestation of vitamin B12 deficiency. It is characterized by microangiopathic hemolytic anemia, reticulocytes, and hematimetric indices that can be normal or that might present a mild megaloblastosis, and which are associated with neurological manifestations. Vitamin B12 can be found in animal-based protein foods. Breastfeeding is an adequate source of this vitamin for children, when maternal serum levels are normal. The case of a 16-month-old infant is presented. She was admitted for hemolytic anemia with transfusion requirement, thrombocytopenia, failure to thrive and developmental delay. During her hospitalization, she was diagnosed with pseudothrombotic microangiopathy caused by vitamin B12 deficiency.

Síndrome hemolítico urémico en una mujer adulta mayor: reporte de caso y revisión de la literatura / Hemolytic uremic syndrome in an older adult woman: case report and literature review

El síndrome hemolítico urémico (SHU) típico en adultos es una patología infrecuente. En la literatura se encuentran pocos reportes, y se ha documentado principalmente en la población pediátrica. Esta entidad se caracteriza por ser una microangiopatía trombótica (MAT) que compromete de manera característica los riñones. Es causada usualmente por la infección por Escherichia coli productora de toxina Shiga (STEC), específicamente el serotipo O157:H7. En Colombia no existen casos reportados sobre esta condición en adultos, lo cual llama la atención, pero puede deberse en parte a las dificultades en su diagnóstico, al no tenerse fácil acceso a algunas de las pruebas que orientan hacia esta enfermedad y confirman el diagnóstico. Se reporta el caso de una mujer adulta mayor colombiana, quien consultó por deposiciones diarreicas y hematoquecia, con el posterior desarrollo de trombocitopenia severa, lesión renal aguda, y evidencia de equinocitos y esquistocitos en extendido de sangre periférica, lo que llevó a sospechar una MAT. Se le solicitó FilmArray® gastrointestinal, el cual fue positivo para STEC, confirmando así el diagnóstico de un SHU típico. Se presenta también una breve revisión del tema de una entidad que requiere un diagnóstico temprano y certero que permita brindar un tratamiento eficaz y oportuno

The classic or typical hemolytic uremic syndrome (HUS) in adults is a rare disease. Few reports are found in the literature, and it has mainly been documented in the pediatric population. This condition is a form of thrombotic microangiopathy (TMA), which characteristically compromises the kidneys. It is mainly caused by infection with Shiga toxin-producing Escherichia coli (STEC), specifically the O157:H7 serotype. In Colombia there are no reports on this condition in adults, and may be due in part to difficulties in its diagnosis, as there is not easy access to some of the tests that guide towards this condition and confirm the diagnosis. The case of an elderly Colombian woman is reported, who presented diarrhea and hematochezia, and subsequently developed severe thrombocytopenia and acute kidney injury, with evidence of echinocytes and schistocytes in peripheral blood smears, which led to suspect TMA. A gastrointestinal FilmArray™ was ordered, which was positive for STEC, thus confirming the diagnosis of a typical HUS. A brief literature review is also presented, which covers general concepts of a condition that requires an early and accurate diagnosis in order to provide an effective and timely treatment

Microangiopatías trombóticas primarias: una revisión narrativa / Primary thrombotic microangiopathies: a narrative review

La microangiopatía trombótica (MAT) es un síndrome donde hay formación de microtrombos en la circulación que llevan a anemia hemolítica microangiopática (AHMA) y trombocitopenia con falla multiorgánica, debido a la isquemia de los tejidos. Las MAT pueden ser primarias sin causa subyacente asociada, como la púrpura trombocitopénica trombótica debida a deficiencia de la enzima ADAMTS13, el síndrome hemolítico urémico debido a la toxina Shiga de Escherichia coli enterohemorrágica, y la MAT producida por alteraciones en la regulación del complemento. Adicionalmente, pueden ser secundarias a enfermedades malignas, infecciosas, metabólicas, autoinmunes o inducidas por el embarazo. Estas patologías requieren diagnóstico y tratamiento oportunos debido a que tienen alta morbimortalidad y se asocian a complicaciones que incluyen enfermedad renal, alteraciones neurológicas como convulsiones, accidente cerebrovascular, coma y muerte. El tratamiento es multidisciplinario y se enfoca en el soporte hemodinámico, transfusional y en el manejo de la etiología cuando esta es identificada. La siguiente revisión pretende explicar de forma clara y precisa los aspectos generales de las MAT primarias

Thrombotic microangiopathy (TMA) is a syndrome characterized by the formation of microthrombi in the circulation leading to microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, with multiorgan failure due to tissue ischemia. TMA can be primary with no associated underlying cause, such as thrombotic thrombocytopenic purpura due to ADAMTS13 deficiency, hemolytic uremic syndrome due to the Shiga toxin from enterohemorrhagic Escherichia coli, or due to complement dysregulation. Furthermore, TMA can be secondary to malignant, infectious, metabolic or autoimmune diseases, or induced by pregnancy. These conditions require a timely diagnosis and treatment due to their associated high morbidity and mortality, and complications like renal disease, neurological disorders such as seizures, stroke, coma and death. Treatment is multidisciplinary and focuses on hemodynamic and transfusion support, and on the management of the etiology when it is identified (daily plasma exchange, eculizumab or management of underlying disease). This review aims to discuss the general aspects of primary thrombotic microangiopathies

Microangiopatía trombótica en el trasplante renal, el tacrolimus como causante / Thrombotic microangiopathy in renal transplantation, tacrolimus as a causative agent

RESUMEN La microangiopatía trombótica (MAT) es una complicación poco frecuente asociada al uso de tacrolimus en el trasplante renal. Puede estar relacionado a infecciones, rechazo mediado por anticuerpos (RMA), recurrencia de enfermedad o MAT de novo y a toxicidad por inhibidores de la calcineurina. Por lo general, se presenta como formas incompletas, lo que hace difícil su diagnóstico, por lo que puede provocar lesiones irreversibles. El caso presentado comparte la presencia de infección viral, datos sugerentes de rechazo concomitantemente con el uso de tacrolimus. El tratamiento incluye plasmaferesis y anticuerpos monoclonales como eculizumab. Sin embargo, en el caso presentado la suspensión o cambio del tacrolimus fue una medida más costo-efectiva.

ABSTRACT Thrombotic microangiopathy (TMA) is an unusual complication associated to the use of tacrolimus in renal transplantation. This condition may be related to infections, antibody-mediated rejection (AMR), disease recurrence or de novo TMA, and toxicity of calcineurin inhibitors. Generally, this condition presents in non-complete forms, which makes diagnosis difficult, and irreversible lesions may supervene. This case features the presence of a viral infection, and data suggesting rejection with the concomitant tacrolimus use. Therapy includes plasmapheresis and the use of monoclonal antibodies such as eculizumab. Nonetheless, in this particular case suspending therapy or switching from tacrolimus to another agent were good cost-effective measures.

Biomarcadores y blancos moleculares del complemento en el diagnóstico de las microangiopatías trombóticas / Complement biomarkers and molecular targets in the diagnosis of thrombotic microangiopathies / Biomarcadores e alvos moleculares do complemento no diagnóstico das microangiopatias trombóticas

Resumen El sistema del complemento juega un papel central en la inmunidad innata, es una línea de defensa contra patógenos y participa en la homeostasis. La activación anormal del complemento contribuye al desarrollo de patologías de variable severidad, tanto inmunológicas y hematológicas como renales. Entre ellas, las microangiopatías trombóticas (MAT) representan un grupo de enfermedades raras con manifestaciones clínicas comunes caracterizadas por anemia hemolítica no inmune, trombocitopenia y daño de órgano(s) blanco. Si bien la clasificación de las MAT sigue siendo desafiante y no ha sido internacionalmente estandarizada, la descripción de entidades asociadas a anomalías del complemento fue comprobada con la eficiencia de la terapia anticomplemento en los pacientes. Las herramientas de diagnóstico desarrolladas en las últimas décadas son esenciales actualmente para diferenciar las MAT más características del grupo; esto es, la púrpura trombótica trombocitopénica (PTT) y el síndrome urémico hemolítico (SUH). En el presente trabajo se presenta una revisión del funcionamiento del sistema del complemento en condiciones fisiológicas, para poder explicar luego cuáles son las alteraciones del sistema implicadas en el desarrollo de las MAT y describir las herramientas disponibles para detectarlas en el laboratorio.

Abstract The complement system plays a crucial role in the innate immune response, being the first-line defense against pathogens and regulating homeostasis. Uncontrolled complement activation can cause immunologic, hematologic as well as renal syndromes of variable severity. Among them, thrombotic microangiopathies (TMA) represent a group of rare diseases characterised by similar clinical manifestations such as microangiopathic hemolytic anemia (MAHA), peripheral thrombocytopenia and organ injury. Although TMA classification is still challenging and no international consensus has been reached, complement-associated disorders have been described thanks to the efficiency of anti-complement therapy in patients. Diagnostic tools developed in the last decades are essential to differentiate the two most well characterized TMA: thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). This review will describe how the complement system works in physiological conditions in order to explain how complement abnormalities are involved in TMA, and finally how to detect those anomalies using laboratory tests.

Resumo O sistema do complemento desempenha um papel central na imunidade inata, sendo uma linha de defesa contra patógenos e participando da homeostase. A ativação anormal do complemento contribui para o desenvolvimento de patologias de gravidade variável, como imunológicas, hematológicas e renais. Entre elas, as microangiopatias trombóticas (MAT) representam um grupo de doenças raras com manifestações clínicas comuns caracterizadas por anemia hemolítica não imune, trombocitopenia e lesão de órgão(s) alvo. Embora a classificação das MAT continue sendo desafiadora e não tenha sido padronizada internacionalmente, a descrição de entidades associadas a anomalias do complemento foi comprovada com a eficiência da terapia anticomplemento nos pacientes. As ferramentas de diagnóstico desenvolvidas nas últimas décadas são atualmente essenciais para diferenciar as MAT mais características do grupo, que são a púrpura trombocitopênica trombótica (PTT) e a síndrome hemolítica urêmica atípica (SHU). Neste trabalho, é apresentada uma revisão do funcionamento do sistema de complemento em condições fisiológicas, a fim de explicar posteriormente quais são as alterações do sistema compreendidas no desenvolvimento das MAT, e descrever as ferramentas disponíveis para detectá-las em laboratório.

Doença de Coronavírus-19 e o Miocárdio / Coronavirus Disease 2019 and the Myocardium

Resumo A infecção pelo coronavírus denominada COVID-19 promoveu crescente interesse de cardiologistas, emergencistas, intensivistas e pesquisadores, pelo estudo do acometimento miocárdico partindo de diferentes formas clínicas decorrentes de desmodulação imunoinflamatória e neuro-humoral.O acometimento miocárdico pode ser mínimo e apenas identificado a partir de alterações eletrocardiográficas, principalmente por aumento de troponinas cardíacas, ou no outro lado do espectro pelas formas de miocardite fulminante e síndrome de takotsubo.A descrição de provável miocardite aguda tem sido comumente apoiada pela observação da troponina elevada em associação com disfunção. A clássica definição de miocardite, respaldada pela biópsia endomiocárdica de infiltrado inflamatório é rara, e foi observada em um único relato de caso até o momento, não se identificando o vírus no interior dos cardiomiócitos.Assim, o fenômeno que se tem documentado é de injúria miocárdica aguda, sendo obrigatório afastar doença coronária obstrutiva a partir da elevação de marcadores de necrose miocárdica, associada ou não à disfunção ventricular, provavelmente associada à tempestade de citoquinas e outros fatores que podem sinergicamente promover lesão miocárdica, tais como hiperativação simpática, hipoxemia, hipotensão arterial e fenômenos trombóticos microvasculares.Fenômenos inflamatórios sistêmicos e miocárdicos após infecção viral estão bem documentados, podendo evoluir para remodelamento cardíaco e disfunção miocárdica. Portanto, será importante a cardiovigilância desses indivíduos para monitorar o desenvolvimento do fenótipo de miocardiopatia dilatada.A presente revisão apresenta os principais achados etiofisiopatológicos, descrição da taxonomia desses tipos de acometimento cardíaco e sua correlação com as principais formas clínicas do componente miocárdico presente nos pacientes na fase aguda de COVID-19.

Abstract Infection with the coronavirus known as COVID-19 has promoted growing interest on the part of cardiologists, emergency care specialists, intensive care specialists, and researchers, due to the study of myocardial involvement based on different clinical forms resulting from immunoinflammatory and neurohumoral demodulation.Myocardial involvement may be minimal and identifiable only by electrocardiographic changes, mainly increased cardiac troponins, or, on the other side of the spectrum, by forms of fulminant myocarditis and takotsubo syndrome.The description of probable acute myocarditis has been widely supported by the observation of increased troponin in association with dysfunction. Classical definition of myocarditis, supported by endomyocardial biopsy of inflammatory infiltrate, is rare; it has been observed in only one case report to date, and the virus has not been identified inside cardiomyocytes.Thus, the phenomenon that has been documented is acute myocardial injury, making it necessary to rule our obstructive coronary disease based on increased markers of myocardial necrosis, whether or not they are associated with ventricular dysfunction, likely associated with cytokine storms and other factors that may synergistically promote myocardial injury, such as sympathetic hyperactivation, hypoxemia, arterial hypotension, and microvascular thrombotic phenomena.Systemic inflammatory and myocardial phenomena following viral infection have been well documented, and they may progress to cardiac remodeling and myocardial dysfunction. Cardiac monitoring of these patients is, therefore, important in order to monitor the development of the phenotype of dilated myocardiopathy.This review presents the main etiological and physiopathological findings, a description of the taxonomy of these types of cardiac involvement, and their correlation with the main clinical forms of the myocardial component present in patients in the acute phase of COVID-19.

Coronavirus 229E with Rhinovirus co-infection causing severe acute respiratory distress syndrome with thrombotic microangiopathy and death during Covid-19 pandemic: lessons to be learnt

We report on a 3-month old infant male who had a seven-days history of fever and rhinorrhea associated with wheezing prior to his death, during the Covid-19 pandemic. Viral testing for Covid-19 (SARS-CoV-2) was negative but was positive for Coronavirus 229E and RP Human Rhinovirus. The pulmonary histological examination showed diffuse alveolar damage along with thrombotic microangiopathy affecting alveolar capillaries. Also, thrombotic microangiopathy was evident in the heart, lungs, brain, kidneys and liver. Thrombotic microangiopathy is a major pathologic finding in Acute Respiratory Distress Syndrome and in the multiorgan failure. This is the first report that illustrates thrombotic microangiopathy occurring in lung, heart, liver, kidney and brain in Acute Respiratory Distress Syndrome with Coronavirus 229E with Rhinovirus co-infection. The clinical presentation and pathological findings in our case share common features with Covid-19.

Atypical hemolytic-uremic syndrome (aHUS) / Síndrome hemolítico urémico atípico (SHUa)

Abstract Atypical hemolytic-uremic syndrome (aHUS) is a diagnosis of exclusion which should be proposed in cases where there is microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. It is associated with mutations which cause dysregulation of the complement system and implies an adverse prognosis and a high risk of progression to chronic kidney disease. Following, we present the case of a patient with aHUS, highlighting the effect and importance of biologic therapy with the monoclonal antibody eculizumab. (Acta Med Colomb 2019; 44. DOI:https://doi.org/10.36104/amc.2019.1301).

Resumen El síndrome hemolítico urémico atípico (SHUa) constituye un diagnóstico de exclusión que debe plantearse ante la presencia de anemia hemolítica microangiopática, trombocitopenia y lesión renal aguda. Está asociado con mutaciones que provocan una disregulación del sistema del complemento e implica un pronóstico adverso y alto riesgo de progresión a enfermedad renal crónica. A continuación, presentamos el caso de un paciente con SHUa resaltando el efecto e importancia de la terapia biológica con el anticuerpo monoclonal eculizumab. (Acta Med Colomb 2019; 44. DOI:https://doi.org/10.36104/amc.2019.1301).

Renal histological findings in a patient with acute renal injury associated with purpura fulminans: a case report / Achados histológicos renais em paciente com injúria renal aguda associada à purpura fulminans: relato de caso

ABSTRACT Introduction: Purpura fulminans (PF) is a rapid progressive thrombotic disease in which hemorrhagic infarction of the skin and disseminated intravascular coagulation (DIC) occurs. It can potentially cause acute kidney injury (AKI). However, there is no description in the medical literature of renal histological findings of PF. Case report: A 20-year-old female patient, previously healthy, was admitted to the emergency department (ED) with odynophagia, fever, generalized myalgia and anuria, which evolved with the appearance of purpuric plaques on the face and limbs. She required dialysis on admission. Laboratorial tests showed anemia, leukocytosis, thrombocytopenia, and elevation of lactic dehydrogenase (LDH). The purpuric lesions became bullous with ruptures and then necrotic and erosive, reaching the dermis, subcutaneous tissue and musculature, until bone exposure. There was no improvement with initial antibiotic therapy aimed at the treatment of meningococcemia. Thrombotic microangiopathy (TMA) and PF were then suspected. The patient remained in daily dialysis, requiring plasmapheresis. After sustained improvement of the thrombocytopenia, she underwent renal biopsy, which was not compatible with TMA, characterizing possible PF. A complete recovery of the renal function was achieved and cutaneous sequels were treated with grafts. Conclusion: When thrombotic and hemorrhagic phenomena overlap, obtaining a renal biopsy can be difficult. However, in the presented case, the biopsy allowed the exclusion of AKI caused by TMA, presenting for the first time, histological findings compatible with PF.

RESUMO Introdução: Purpura Fulminans (PF) é uma doença trombótica de rápida progressão, com infarto hemorrágico da pele e coagulação intravascular disseminada (CIVD). É potencialmente causadora de injúria renal aguda (IRA). Porém, não há descrição na literatura médica dos achados histológicos renais causados por PF. Relato de caso: Mulher, 20 anos, previamente hígida, hospitalizada por odinofagia, febre, mialgia generalizada e anúria, evoluiu com aparecimento de placas purpúricas em face e membros. Necessitou de hemodiálise (HD) já na admissão. Exames laboratoriais mostravam anemia, leucocitose, plaquetopenia e elevação de desidrogenase lática. As lesões purpúricas tornaram-se bolhosas com rompimento e progressão para necrose, se aprofundaram, atingindo derme, subcutâneo e musculatura, até a exposição óssea. Não houve melhora com antibioticoterapia inicial voltada para tratamento de meningococemia. Suspeitou-se, então, de microangiopatia trombótica (MAT) e PF. A paciente permaneceu em HD diária e necessitou também de plasmaférese, após melhora sustentada da plaquetopenia, foi submetida à biópsia renal, que não foi compatível com MAT, possivelmente caracterizando PF. Houve recuperação completa da função renal e as sequelas cutâneas foram tratadas com enxerto. Conclusão: Em casos nos quais os fenômenos trombóticos e hemorrágicos se sobrepõem, a obtenção da biópsia renal se torna difícil. Neste caso, a biópsia permitiu excluir IRA causada por MAT e mostrar, pela primeira vez, achados compatíveis com PF.

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.