HELLP syndrome and hemolytic uremic syndrome during pregnancy: two disease entities, same causation. Case report and literature review

Abstract

Abstract

Thrombotic microangiopathies (TMA) are a group of diseases that can complicate pregnancy and threaten the lives of both the mother and the fetus. Several conditions can lead to TMA, including thrombotic thrombocytopenic purpura (TTP), HELLP syndrome and hemolytic uremic syndrome (HUS). We describe the case of a 39-year-old woman who presented a HELLP syndrome in the immediate postpartum period. The patient had acute kidney injury (AKI), increased LDH, unmeasurable haptoglobin levels and hypocomplementemia. Her ADAMTS13 value was normal, thus ruling out TTP. Shiga toxin tests were negative, so HUS associated with E. coli was also ruled out. HELLP syndrome and atypical hemolytic-uremic syndrome (aHUS) remained the most probable diagnosis. In the days following childbirth, the patient’s transaminase and bilirubin levels normalized while the anemia persisted, as did the AKI, resulting in the institution of dialysis treatment. A diagnosis of aHUS was made and therapy with eculizumab was started. The patient’s blood counts progressively improved, urine output was restored, her indices of renal function also concomitantly improved and dialysis was interrupted. A rash appeared after the third administration of eculizumab and the treatment was suspended. The patient is currently being followed up and has not relapsed. At thirteen months after delivery her renal function is normal as are her platelet counts, LDH, haptoglobin levels and proteinuria. Tests for mutations in the genes that regulate complement activity were negative. We believe that childbirth triggered the HELLP syndrome, which in turn brought about and sustained the HUS. In fact, the patient’s liver function improved right after delivery, while her kidney injury and hemolysis persisted, and she also had an excellent response to eculizumab. To our knowledge, no other cases of HELLP syndrome associated with haemolytic uremic syndrome during pregnancy have been reported in literature, nor have cases in which treatment with eculizumab was limited to only three administrations.

Keywords: HELLP syndrome, hemolytic uremic syndrome, pregnancy, eculizumab, thrombotic microangiopathy

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Introduzione

Le microangiopatie trombotiche (MAT) rappresentano un eterogeneo gruppo di affezioni che possono complicare la gravidanza mettendo a rischio la vita della madre e del feto. Tra di esse troviamo la porpora trombotica trombocitopenica (PTT), la sindrome HELLP e la sindrome emolitica uremica (SEU), tutte caratterizzate da un danno a carico delle cellule endoteliali e trombosi dei piccoli vasi che si manifestano clinicamente con anemia emolitica, trombocitopenia, e danno d’organo [13]. I confini tra queste patologie non sono ben definiti tanto che può essere difficile o addirittura impossibile una diagnosi differenziale, considerando poi che dette condizioni possono coesistere [48]. A complicare ulteriormente l’iter diagnostico, durante la gravidanza i parametri ematologici [9], della proteinuria [10] e della concentrazione del complemento hanno range di riferimento differenti rispetto al soggetto non in gravidanza [11-12]. 

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The unusual couple: a clinical case of coexistence between aHUS and Fabry’s disease

Abstract

Atypical hemolytic-uremic syndrome (aHUS) is a rare, potentially lethal (14) systemic disorder, capable of affecting both adults and children, causing thrombotic microangiopathy (TMA) (5) that leads to the formation of thrombus within small blood vessels with multiple organ failure. The pathogenesis of the aHUS is part of a sort of chronic and uncontrolled activation of the complement system by genetic mutation of some proteins usually responsible for its self-regulation (6,7). Today, the rapid diagnosis of the disease and the timely start of treatment with eculizumab, improve outcomes of renal failure, stroke and heart attack (810).

Fabry disease is a rare tesaurismosis, X linked, due to the deficiency of the lysosomal enzyme alpha-galactosidase A (11-13), necessary for the physiological catabolism of glycosphingolipids. Multisystem clinical manifestations lead to a serious degenerative pathology. The diagnostic suspicion based on anamnesis and careful research of the symptoms and then confirmed by the enzymatic dosage of alpha galactosidase or by molecular analysis, allows the early treatment of the patient with enzyme replacement therapy, guaranteeing the resolution and/or slowing down the evolution of the disease, especially in the brain, heart and kidneys.

In this report, we describe the clinical case of a patient who is a carrier of both rare diseases.

 

Keywords: aHUS, eculizumab, Fabry’s disease, alpha galactosidase, enzyme replacement therapy

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Caso clinico

Riportiamo il caso clinico di una paziente nata nel 1980, prima di due sorelle, in riferita a.b.s fino a gennaio del 2001, epoca in cui presentò un episodio di macroematuria, trattato con terapia antibiotica per sospetta cistite emorragica. Dopo un mese, all’esame delle urine, presentava ancora microematuria. Nel corso del 2001 continuò a lamentare astenia, attribuita allo stress per lo studio e al contemporaneo lavoro di modella, ma non fu sottoposta ad ulteriori esami ematici.  

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Atypical Hemolytic Uremic Syndrome: experience of a pediatric center

Abstract

In the last two years we admitted in our Hospital  38 children with acute renal failure (ARF). Six of them were affected by hemolytic uremic syndrome (HUS) atypical. The aHUS is diagnosed in the presence of thrombotic microangiopathy (MAT), renal insufficiency (GFR 5%).

The clinical presentation of our children has been varied and so also its evolution. Patients observed were all male, aged 2 to 12 years, and no one had a family history of kidney disease. In four patients we documented alterations of complement factors (MCP deficiency and factor H and presence of anti factor H). Repeated blood transfusions were required in 4 patients and in 3 patients the platelet count was slightly reduced. In 5 patients we did plasmapheresis and in 3 patients dialysis (hemodialysis and peritoneal dialysis). In three patients in whom the diagnosis was not clear, renal biopsy was performed to confirm the diagnosis. Eculizumab was administered in 3 patients resistant to plasma exchange. We obtain a rapid response on MAT with normalization of platelet count. The effect on renal function was variable (complete remission in a patient, partial improvement in another, and unresponsiveness in the last). The last had on Kidney biopsy signs of severe impairment and we documented the presence of antibodies to eculizumab. HUS is a rare condition, but probably much more common than reported. In children with ARF and microangiopathic anemia is necessary evaluated  complement factors as early to obtain an improved clinical response to treatment with eculizumab.

Keywords: atypical hemolytic uremic syndrome, acute renal failure, pediatric, eculizumab.

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Introduzione

La sindrome emolitico uremica atipica (aSEU) è una rara forma di microangiopatia trombotica dalle manifestazioni cliniche pleiotropiche. Essa è caratterizzata da insufficienza renale acuta (IRA), anemia emolitica (AE), piastrinopenia, assenza di Shiga-toxin nelle feci (a differenza della SEU tipica) e con livello di ADAMTS-13 superiore al 5%, contrariamente alla porpora trombotica trombocitopenica idiopatica con cui la aSEU presenta delle analogie (1). 

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ATYPICAL HEMOLITIC UREMIC SYNDROME AFTER ADMINISTRATION OF DOCETAXEL

Abstract

The purpose of this study is to describe the clinical case of a patient suffering from a gland carcinoma with bilateral inguinal and pelvic lymph node metastases in treatment with weekly administrations of Docetaxel.
After two therapy cycles, the patient developed an atypical uremic hemolytic Syndrome (SEUa), treated with infusions of frozen fresh plasma, hemodialysis, and antibiotics.
Because of a severe septic secondary complication on an extensive lymph node abscess, the administration of Eculizumab was not possible.
The patient survived the mentioned Syndrome and is currently in periodic dialysis treatment.

Keywords: aHUS, Docetaxel, Eculizumab

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Introduzione

Il Docetaxel, un taxanosemi-sintetico di seconda generazione, è un antineoplastico caratterizzato da un ampio spettro di proprietà antitumorali. Il suo principale meccanismo d’azione consiste nel legarsi e stabilizzare la tubulina inibendo così lo smontaggio del microtubulo e provocando l’arresto del ciclo cellulare alla fase G2/M e quindi la morte cellulare. Questo farmaco inibisce diversi fattori pro-angiogenetici come il fattore di crescita endoteliale vascolare (VEGF) e presenta proprietà immuno-modulatorie e pro-infiammatorie per stimolazione di diversi mediatori della risposta infiammatoria. Il Docetaxel è approvato dalla “Food and Drug Administration” (FDA), in mono-terapia o associato ad altri chemioterapici, per il trattamento dei tumori al seno, non a piccole cellule del polmone, prostatico refrattario alla terapia ormonale, a cellule squamose del capo e del collo e dell’adenocarcinoma gastrico (1).La SEUa è associata molto raramente alla somministrazione di Docetaxel, anche se sono descritti molti casi con altri chemioterapici (2). Noi descriviamo il caso di SEUa in un paziente affetto da carcinoma squamoso del glande metastatico ai linfonodi loco-regionali dopo trattamento con Docetaxel quale terapia di seconda linea. 

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Membranous glomerulonephritis (MGN), ongoing studies

Abstract

The membranous nephropathy (MN) is the major cause of nephrotic syndrome in in the adult, account for 20% of cases with annual incidence is 1 in 100.000.
In the past 10 years, the role of podocytes has been identified; environmental triggers in genetically predisposed patients can activate podocytes to exhibit antigenic epitopes (receptor of phospholipase A2, thrombospondin type 1) that become targets of specific autoantibodies with subsequent complement activation. The discovery of this mechanisms has opened new horizons in the therapy of MN and novel drugs are available with more specific mechanism of action.
Rituximab, a monoclonal antibody directed against CD20 expressed by lymphocytes B, has been used in several trials and appears able to induce remission of nephrotic syndrome in 60% of patients (GEMRITUX trial) with similar risk profile. Nowadays it remains to define the most effective therapeutic pattern.
In MN, the concept of targeting disease control, has permit novel therapies with specific blocking mechanisms (belimumab) and non-specific (ACTH) and new therapeutic options, such as ofatumumab, bortezomib and eculizumab, that have allowed to recognize pathological processes involved in the glomerular diseases.

Key Words: Membranous Glomerulonephritis, membranous nephropathy, Rituximab, ECULIZUMAB

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Background

La glomerulonefrite membranosa (GMN) è diagnosticata nel 20% dei casi di sindrome nefrosica dell’adulto, la sua incidenza annuale è di 1 caso ogni 100.000 per anno, vengono diagnosticati quindi 10.000 nuovi casi all’anno in Europa (1).

Negli ultimi 10 anni ne sono stati definiti i precisi meccanismi patogenetici che hanno aperto nuovi scenari di trattamento.

Cosa c’è quindi di nuovo e sostanziale nella nefropatia membranosa?

In sintesi la novità degli ultimi anni è che tale glomerulonefrite è una malattia del podocita che, probabilmente in risposta a stimoli ambientali non ancora chiaramente identificati e su una potenziale predisposizione genetica, espone epitopi di antigeni che diventano bersaglio di anticorpi che determinano attivazione del complemento.

Queste acquisizioni hanno avviato dal punto vista della ricerca una serie di vie per la comprensione dei meccanismi caratterizzanti lo sviluppo della malattia. Sono diventati quindi oggetto di studio i marcatori podocitari in grado di attivare il sistema immunitario, le cellule che producono anticorpi diretti contro gli antigeni esposti e la via di attivazione del complemento (23).
 

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