The Differential Diagnosis and Treatment of Thrombotic Microangiopathies.

BACKGROUND: Thrombotic microangiopathies are rare, life-threatening diseaseswhose care involves physicians from multiple specialties. The past five years haveseen major advances in our understanding of the pathophysiology, classification,and treatment of these conditions. Their timely diagnosis and prompt treatment cansave lives. METHODS: This review is based on pertinent articles published up to 17 December2017 that were retrieved by a selective search of the National Library of Medicine'sPubMed database employing the terms "thrombotic microangiopathy," "thromboticthrombocytopenic purpura," "hemolytic-uremic syndrome," "drug-induced TMA," and"EHEC-HUS." RESULTS: The classic types of thrombotic microangiopathy are thrombotic thrombo -cytopenic purpura (TTP) and typical hemolytic-uremic syndrome (HUS), also knownas enterohemorrhagic Escherichia coli-associated HUS (EHEC-HUS). There are anumber of further types from which these must be differentiated. The key test,beyond a basic hematological evaluation including a peripheral blood smear, ismeasurement of the blood level of the protease that splits von Willebrand factor,which is designated ADAMTS13 (a disintegrin and metalloprotease with thrombo -spondin type 1 motif, member 13). The quantitative determination of ADAMTS13, ofADAMTS13 activity, and of the ADAMTS13 inhibitor serves to differentiate TTP fromother types of thrombotic microangiopathy. As TTP requires urgent treatment,plasmapheresis should be begun as soon as TTP is suspected on the basis of afinding of hemolysis with schistocytes and thrombocytopenia. The treatment shouldbe altered as indicated once the laboratory findings become available. CONCLUSION: Rapid differential diagnosis is needed in order to determine the specifictype of thrombotic microangiopathy that is present, because only patients with TTPand only a very small percentage of those with atypical hemolytic-uremic syndrome(aHUS) can benefit from plasmapheresis. The establishment of a nationwideregistry in Germany with an attached biobank might help reveal yet unknowngenetic predispositions.

Where are we with haemolytic uremic syndrome? / Síndrome hemolítico urémico: estado actual.

Haemolytic uremic syndrome (HUS) is characterised by microangiopathic haemolytic anaemia with acute kidney injury. It is currently classified into two main categories: Shiga-toxin producing E. coli-hemolytic uremic syndrome (STEC-HUS) and atypical haemolytic uremic syndrome (aHUS). Endothelial cell damage is the common pathway in HUS to developing thrombotic microangiopathy. Atypical HUS includes primary, secondary and aHUS due to metabolic diseases. In the majority of aHUS cases, hyperactivity of the alternative complement pathway plays a central role. Therefore, treatment is based on complement inhibitors like eculizumab, a drug that has revolutionised the natural history of the disease. Relapses are frequent after kidney transplant and thus confer a poor prognosis.

[Atypical hemolytic uremic syndrome (aHUS): new insights into pathogenesis leading to novel therapeutic approaches]. / Das atypische hämolytisch-urämische Syndrom (aHUS): neue Erkenntnisse zur Pathogenese mit Implikationen für die Therapie.

The atypical hemolytic-uremic syndrome (aHUS) belongs to the thrombotic mictroangiopathies (TMA). This group of diseases has traditionally been divided on clinical grounds by affected organs into thrombotic-thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS), the latter being termed atypical if not preceeded by diarrhea. Tremendous scientific advances of the last two decases have shown that these clinically overlaping syndromes are caused by distinct molecular mechanisms. The definition of clinical syndromes has therefore been replaced by a TMA-classification on a molecular-mechanistic basis. aHUS is caused by an uncontrolled activation of the alternative complement pathway mostly due to genetic defects. These insights and particularly the development of a specific terminal complement inhibitor have revolutionized the treatment of aHUS and considerably improved its prognosis.

An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document.

Haemolytic uraemic syndrome (HUS) is a clinical entity defined as the triad of nonimmune haemolytic anaemia, thrombocytopenia, and acute renal failure, in which the underlying lesions are mediated by systemic thrombotic microangiopathy (TMA). Different causes can induce the TMA process that characterizes HUS. In this document we consider atypical HUS (aHUS) a sub-type of HUS in which the TMA phenomena are the consequence of the endotelial damage in the microvasculature of the kidneys and other organs due to a disregulation of the activity of the complement system. In recent years, a variety of aHUs-related mutations have been identified in genes of the the complement system, which can explain approximately 60% of the aHUS cases, and a number of mutations and polymorphisms have been functionally characterized. These findings have stablished that aHUS is a consequence of the insufficient regulation of the activiation of the complement on cell surfaces, leading to endotelial damage mediated by C5 and the complement terminal pathway. Eculizumab is a monoclonal antibody that inhibits the activation of C5 and blocks the generation of the pro-inflammatory molecule C5a and the formation of the cell membrane attack complex. In prospective studies in patients with aHUS, the use of Eculizumab has shown a fast and sustained interruption of the TMA process and it has been associated with significative long-term improvements in renal function, the interruption of plasma therapy and important reductions in the need of dialysis. According to the existing literature and the accumulated clinical experience, the Spanish aHUS Group published a consensus document with recommendations for the treatment of aHUs (Nefrologia 2013;33[1]:27-45). In the current online version of this document, we update the aetiological classification of TMAs, the pathophysiology of aHUS, its differential diagnosis and its therapeutic management.

Actualización en síndrome hemolítico urémico atípico: diagnóstico y tratamiento. Documento de consenso / An update for atypical haemolytic uraemic syndrome: Diagnosis and treatment. A consensus document

El síndrome hemolítico urémico (SHU) es una entidad clínica definida por la tríada anemia hemolítica no inmune, trombocitopenia e insuficiencia renal aguda, en la que las lesiones subyacentes están mediadas por un proceso de microangiopatía trombótica (MAT) sistémico. Distintas causas pueden desencadenar el proceso de MAT que caracteriza el SHU. En este documento consideramos SHU atípico (SHUa) como el subtipo de SHU en el que los fenómenos de MAT son fundamentalmente consecuencia del daño producido en el endotelio de la microvasculatura renal y de otros órganos por desregulación de la actividad del sistema del complemento. En los últimos años se han identificado diversas mutaciones en genes del sistema del complemento asociados a SHUa, que explicarían aproximadamente el 60% de los casos de SHUa, y se han caracterizado funcionalmente numerosasmutaciones y polimorfismos asociados a SHUa que han permitido determinar que la patología se produce como consecuencia de la deficiente regulación de la activación del complemento sobre las superficies celulares y que lleva al daño endotelial mediado por la activación del C5 y de la vía terminal del complemento. Eculizumab es un anticuerpo monoclonal humanizado que inhibe la activación del C5, bloqueando la generación de la molécula proinflamatoria C5a y la formación del complejo de ataque de membrana. En estudios prospectivos en pacientes con SHUa su administración ha demostrado la interrupción rápida y sostenida del proceso de MAT, con una mejora significativa de la función renal a largo plazo y una reducción importante de la necesidad de diálisis y el cese de la terapia plasmática. En función de las evidencias científicas publicadas y la experiencia clínica acumulada, el Grupo Español de SHUa publicamos un documento de consenso con recomendaciones para el tratamiento de la enfermedad (Nefrología 2013;33(1):27-45). En la presente versión online del documento se actualizan los contenidos sobre la clasificación etiológica de las MAT, la fisiopatología del SHUa, su diagnóstico diferencial y su manejo terapéutico (AU)

Haemolytic uraemic syndrome (HUS) is a clinical entity defined as the triad of nonimmune haemolytic anaemia, thrombocytopenia, and acute renal failure, in which the underlying lesions are mediated by systemic thrombotic microangiopathy (TMA). Different causes can induce the TMA process that characterizes HUS. In this document we consider atypical HUS (aHUS) a sub-type of HUS in which the TMA phenomena are the consequence of the endotelial damage in the microvasculature of the kidneys and other organs due to a disregulation of the activity of the complement system. In recent years, a variety of aHUs-related mutations have been identified in genes of the the complement system, which can explain approximately 60% of the aHUS cases, and a number ofmutations and polymorphisms have been functionally characterized. These findings have stablished that aHUS is a consequence of the insufficient regulation of the activiation of the complement on cell surfaces, leading to endotelial damage mediated by C5 and the complement terminal pathway. Eculizumab is a monoclonal antibody that inhibits the activation of C5 and blocks the generation of the pro-inflammatory molecule C5a and the formation of the cell membrane attack complex. In prospective studies in patients with aHUS, the use of Eculizumab has shown a fast and sustained interruption of the TMA process and it has been associated with significative long-term improvements in renal function, the interruption of plasma therapy and important reductions in the need of dialysis. According to the existing literature and the accumulated clinical experience, the Spanish aHUS Group published a consensus document with recommendations for the treatment of aHUs (Nefrologia 2013;33[1]:27-45). In the current online version of this document, we update the aetiological classification of TMAs, the pathophysiology of aHUS, its differential diagnosis and its therapeutic management (AU)

Interferón ß, microangiopatía trombótica y síndrome nefrótico / Interferon ß, nephrotic syndrome and thrombotic microangiopathy

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Assessment of KDIGO definitions in patients with histopathologic evidence of acute renal disease.

BACKGROUND AND OBJECTIVES: AKI is a clinical syndrome with various causes involving glomerular, interstitial, tubular, and vascular compartments of the kidney. Acute kidney disease (AKD) is a new concept that includes both AKI and the conditions associated with subacute decreases in GFR (AKD/non-AKI). This study aimed to investigate the correlation between AKI/AKD defined by clinical presentation and diffuse histologic criteria for acute abnormalities based on renal biopsy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All 303 patients who were histologically diagnosed as having acute tubular necrosis (ATN), acute tubulointerstitial nephritis, cellular crescentic GN, acute thrombotic microangiopathy, or complex lesions on renal biopsy from January 2009 to December 2011 were enrolled in the study. The 2012 Kidney Disease Improving Global Outcomes AKD/AKI definitions were applied to classify patients as follows: AKI, AKD/non-AKI, non-AKD, or unclassified. RESULTS: A total of 273 patients (90.1%) met the AKD criteria; 198 patients (65.3%) were classified as having AKI according to serum creatinine (SCr) and urine output criteria. The urine output criteria added 4.3% to the SCr criteria and reclassified 6.7% of the AKI cases into higher stages. Of patients with ATN on pathology, 79.2% met AKI criteria; this was a higher percentage than for those who had other individual pathologic lesions (50%-64%). The major cause of not being defined as having AKI was a slower SCr increase than that required by the definition of AKI (98, 93.3%). Patients with AKI had more severe clinical conditions and worse short-term renal outcome than those in the non-AKI group. CONCLUSIONS: Diffuse, acute abnormality defined by renal biopsy and AKI defined by clinical presentation are two different entities. Most patients who have diffuse acute histologic findings met the criteria for AKD, whereas only two thirds met the definition of AKI.

Inclusion of renal vascular lesions in the 2003 ISN/RPS system for classifying lupus nephritis improves renal outcome predictions.

The 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) pathological classification system of lupus nephritis specified the importance of vascular damage and indicated this should be included in the diagnostic summary. Few pathological studies of lupus nephritis, however, focus on the patterns of renal vascular involvement. Here we assessed renal vascular lesions in lupus nephritis based on the 2003 ISN/RPS classification system and evaluated their association with clinical and pathological data in a large cohort from a single center in China. Among 341 patients with lupus nephritis, 279 were diagnosed with single or multiple renal vascular lesions that included 253 with vascular immune complex deposits, 82 with atherosclerosis, 60 with thrombotic microangiopathy, 13 with noninflammatory necrotizing vasculopathy, and 2 with true renal vasculitis. Patients with thrombotic microangiopathy had the poorest renal outcome. In multivariate Cox hazard analysis after inclusion of renal vascular lesions, the new chronicity index score became a significantly better independent risk factor for renal outcome (hazard ratio 2.32). Thus, renal vascular lesions are common in lupus nephritis and closely correlate with clinical disease activity and renal outcome. Inclusion of a detailed description of renal vascular lesions in the ISN/RPS classification of lupus nephritis may strengthen its predictive value for renal outcome.

Renal thrombotic microangiopathy revisited: when a lesion is not a clinical finding.

Despite advances in the field of thrombotic microangiopathy (TMA) and associated syndromes such as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), they still leave several issues unresolved. For instance, actual diagnostic criteria on which therapeutic decisions rely are relatively narrow and focused on TTP-HUS, with the consequence that non-idiopathic and atypically-presenting TMA are overlooked. In addition, nosologic classifications of TMA disorders have varied substantially over the years, but are still devised from historical rather than mechanistic data. As such, it is perhaps not surprising that even today TMA is erroneously used as an interchangeable term with TTP-HUS, and missed or inappropriately diagnosed on various occasions. Yet, recognizing TMA is of crucial importance given that this lesion often manifests with potentially reversible renal failure. In this editorial, which is presented from a Nephrologist's perspective, we propose that TMA disorders need to be reclassified to include most types of presentations and confirmed or excluded through more elaborate diagnostic approaches.

Current insight into thrombotic thrombocytopenic purpura.

During the last three decades knowledge regarding the pathophysiology of thrombotic thrombocytopenic purpura (TTP) has dramatically increased. The discovery of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13) deficiency in a subset of patients with TTP has been an important milestone. Apart from this, the use of therapeutic plasma exchange has reduced mortality rates in TTP from 80-90% to 10-20%. Nevertheless, TTP remains a possibly lethal disorder, in which early recognition of symptoms remains extremely important. In the last few years some interesting new insights into TTP have arisen. Firstly, promising reports on rituximab in the treatment of refractory and relapsing cases of TTP have been published. Secondly, risk stratification by means of ADAMTS13 deficiency and ADAMTS13 antibodies might lead to a more tailored approach in treating TTP patients.