Thrombotic microangiopathy (TMA) is a syndrome of microangiopathic hemolytic anemia and thrombocytopenia with end-organ dysfunction. Although the advent of plasma exchange, immunosuppression, and ...complement inhibition has improved morbidity and mortality for primary TMAs, the management of secondary TMAs, particularly drug-induced TMA, remains less clear. TMA related to cancer drugs disrupts the antineoplastic treatment course, increasing the risk of cancer progression. Chemotherapeutic agents such as mitomycin-C, gemcitabine, and platinum-based drugs as well as targeted therapies such as antiangiogenesis agents and proteasome inhibitors have been implicated in oncotherapy-associated TMA. Among TMA subtypes, drug-induced TMA is less well-understood. Treatment generally involves withdrawal of the offending agent and supportive care targeting blood pressure and proteinuria reduction. Immunosuppression and therapeutic plasma exchange have not shown clear benefit. The terminal complement inhibitor, eculizumab, has shown promising results in some cases of chemotherapy-associated TMA including in re-exposure. However, the data are limited, and unlike in primary atypical hemolytic uremic syndrome, the role of complement in the pathogenesis of drug-induced TMA is unclear. Larger multicenter studies and unified definitions are needed to elucidate the extent of the problem and potential treatment strategies.
血栓性微小血管症（thrombotic microangiopathy: TMA）は血小板減少，細血管障害性溶血性貧血，血小板血栓による臓器障害を三徴候とする症候群である．様々な病態を包括し，ADAMTS13（a disintegrin-like and metalloproteinase with thrombospondin type 1 motif ...13）活性著減を原因とするもの，補体が関与するもの，背景に何らかの基礎疾患を有する二次性のものなどに分けられる．TMAは診断に難渋する症例も散見されるが，死亡することもあり，適切な治療を速やかに選択することが求められる．近年，TMAの治療は知見が集約したことにより，病因によっては死亡率の改善を認めるものも出現した．病因により使用できる薬剤や治療法が異なるが，血漿交換療法やEculizumabなどの登場により，飛躍的にその死亡率が改善した病型も存在する．Caplacizumabの登場により，ADAMTS13活性低下を原因とするTMAにおいて新たな介入の選択肢が増えたが，先述のとおり，TMAは様々な病因を有する疾患を包括する概念であり，個々の症例において病因に合わせた治療介入が求められる．
A 34-year-old Japanese man presented with blurred vision, headache, nausea, anemia, thrombocytopenia, and severe renal dysfunction. Thrombotic microangiopathy was initially suspected to have been ...caused by malignant hypertension. Antihypertensive medications did not improve his thrombocytopenia or renal dysfunction, and other diseases causing thrombotic microangiopathy were ruled out. Therefore, the patient was diagnosed with atypical hemolytic uremic syndrome. A renal biopsy revealed an overlap of thrombotic microangiopathy and C3 glomerulopathy. Genetic testing revealed c.848A>G (p.Asp283Gly), a missense heterozygous variant in the gene encoding complement factor I. Overlapping atypical hemolytic uremic syndrome and C3 glomerulopathy with complement factor I mutation is very rare, especially in Japan.
Background Atypical hemolytic uremic syndrome (aHUS) is a rare genetic life-threatening disease of chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA) and severe ...end-organ damage. Eculizumab, a terminal complement inhibitor approved for aHUS treatment, was reported to improve hematologic and renal parameters in 2 prior prospective phase 2 studies. This is the largest prospective study of eculizumab in aHUS to date, conducted in an adult population. Study Design Open-label single-arm phase 2 trial. Setting & Participants Patients 18 years or older with aHUS (platelet count <150 × 103 /μL, hemoglobin ≤ lower limit of normal, lactate dehydrogenase ≥1.5 × upper limit of normal ULN, and serum creatinine ≥ ULN) were included in this multicenter multinational study. Intervention Intravenous eculizumab (900 mg/wk for 4 weeks, 1,200 mg at week 5 and then every 2 weeks) for 26 weeks. Outcomes & Measurements Primary end point was complete TMA response within 26 weeks, defined as hematologic normalization (platelet count ≥150 × 103 /μL, LDH ≤ ULN), and preservation of kidney function (<25% serum creatinine increase from baseline), confirmed by 2 or more consecutive measurements obtained 4 or more weeks apart. Results 41 patients were treated; 38 (93%) completed 26 weeks of treatment. 30 (73%) were included during their first TMA manifestation. 30 (73%) had complete TMA response. Platelet counts and estimated glomerular filtration rates increased from baseline ( P < 0.001). All 35 patients on baseline plasma exchange/plasma infusion discontinued by week 26. Of 24 patients requiring baseline dialysis, 5 recovered kidney function before eculizumab initiation and 15 of the remaining 19 (79%) discontinued dialysis during eculizumab treatment. No patients lost existing transplants. Quality-of-life measures were significantly improved. Two patients developed meningococcal infections; both recovered, and 1 remained on eculizumab treatment. Limitations Single-arm open-label design. Conclusions Results highlight the benefits of eculizumab in adult patients with aHUS: improvement in hematologic, renal, and quality-of-life parameters; dialysis discontinuation; and transplant protection.
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•Review article appraises the biochemical and microbiological changes and major volatiles formation in stored fish.•It explores specifically about the protein and lipid breakdown in ...the muscle.•Included chemical, microbiological and physical indicators of fish freshness.•Enriched with recent innovations and developments on freshness indicators and assessment.•It has also made systematic and in-depth information of fish freshness in tabular form.
Fish, a highly nutritious, containing a good amount of protein and fatty acids, has TMA and TVB-N present as major factors responsible for quality deterioration during storage and maintaining of fish freshness. Freshness is one of the most important parameters in the fish market. There are many methods of estimating fish freshness, out of which some are very costly while others are not user-friendly. However, with more technological innovations, there have been efforts to make a more reliable method of calculating and analyzing freshness. Parameters chosen for assessing the freshness are sensory, physical, chemical and microbiological including the recent trends such as SDS-PAGE, fast protein liquid chromatography, hyper Spectral Imaging Technique, etc. focused on reducing time, destruction and labor. Traditional and recent methods of evaluation of freshness along with their comparison based on several parameters are needed to link them and making it convenient for upcoming researchers to have a detailed study for having a universal indicator for assessing the freshness of fish. Information in the present article has all the methods of assessing the fish freshness been discussed in detail. There has also been focus on bringing the readers knowledge about the comprehensive information related to recent developments. The recommended limit for different indicators signifies the time period for which the particular fish can be stored and it depends upon several factors like species, surrounding environment and enzymatic and non-enzymatic actions. Based on these demands, this paper is uniquely worked upon to review the different literature which brought all the discussions from the past including the recent innovations in assessing the freshness of different fishes with the help of various indicators as well as a complete study of spoilage and toxicity mechanism leading to deterioration in quality, making it easy for the reader and researchers to have quick glance over the trends and innovations.
A 34-year-old Japanese man presented with blurred vision, headache, nausea, anemia, thrombocytopenia, and severe renal dysfunction. Thrombotic microangiopathy was initially suspected to have been ...caused by malignant hypertension. Antihypertensive medications did not improve his thrombocytopenia or renal dysfunction, and other diseases causing thrombotic microangiopathy were ruled out. Therefore, the patient was diagnosed with atypical hemolytic uremic syndrome. A renal biopsy revealed an overlap of thrombotic microangiopathy and C3 glomerulopathy. Genetic testing revealed c.848A>G (p.Asp283Gly), a missense heterozygous variant in the gene encoding complement factor I. Overlapping atypical hemolytic uremic syndrome and C3 glomerulopathy with complement factor I mutation is very rare, especially in Japan.
Renal Thrombotic Microangiopathy: A Review Genest, Dominique Suzanne; Patriquin, Christopher J.; Licht, Christoph ...
American journal of kidney diseases,
20/May , Letnik:
81, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Thrombotic microangiopathy (TMA), a pathological lesion observed in a wide spectrum of diseases, is triggered by endothelial injury and/or dysfunction. Although TMA lesions are often accompanied by ...clinical features of microangiopathic hemolytic anemia, thrombocytopenia, and ischemic end-organ injury, renal-limited forms of TMA are not infrequently encountered in clinical practice. The presence of renal-limited manifestations can be diagnostically challenging, often delaying the initiation of targeted therapy. Prompt investigation and empirical treatment of TMA is warranted to reduce associated morbidity and mortality. Major advances have been made with respect to the pathophysiology of primary TMA entities, with the subsequent development of novel diagnostic tools and lifesaving therapies for diseases like thrombotic thrombocytopenic purpura and complement-mediated TMA. This article will review the clinical presentation and pathologic hallmarks of TMA involving the kidney, and the disease-specific mechanisms that contribute to the endothelial injury that characterizes TMA lesions. Diagnostic approach and both empirical and disease-specific treatment strategies will be discussed, along with the potential role for emerging targeted disease-specific therapies.
ADAMTS13 (A Disintegrin and Metalloprotease with ThromboSpondin type 1 motifs) activity is a key tool in differential diagnosis of thrombotic microangiopathies (TMAs). Due to the lack of availability ...of ADAMTS13 testing, PLASMIC/PLASIC scores have been suggested to predict ADAMTS13 deficiency. The importance of differentiating TTP from other complement-mediated TMAs is highlighted by the need to urgently start plasma exchange and utility of treatments such as caplacizumab or eculuzimab. Therefore, we aimed to evaluate ADAMTS13 activity, PLASMIC/PLASIC scores, and complement testing in guiding management of a real-world TMA cohort. We enrolled consecutive TMA patients with samples referred to our Center (01/2018–2020). If ADAMTS13 > 10%, soluble C5b-9 was measured. Among 80 TMA patients, ADAMTS13 activity was ≤10% in 50 patients, while 28 had a relapsing disease. PLASMIC/PLASIC were excellent predictors of ADAMTS13 deficiency, especially in patients without secondary causes. Soluble C5b-9 levels were elevated (median 525 ng/ml, range 313–913 ng/ml) in 7 patients without secondary causes and ADAMTS13 > 10% (hemolytic uremic syndrome/HUS). Two were shiga-toxin associated; while 5 atypical HUS. Only 1/5 patients received eculizumab and achieved TMA resolution implemented by guidance based on soluble C5b-9 levels. In transplant-associated TMA, 8/16 patients not responding to first-line treatment received eculizumab due to elevated C5b-9 levels (median 353 ng/ml, range 281–1252 ng/ml) and achieved TMA resolution. In conclusion, our real-world data confirm that ADAMTS13, complement testing, and PLASMIC/PLASIC are valuable tools in diagnosis and management of TMAs, but also highlight the unmet need of using available markers and treatments in clinical practice.
•PLASMIC/PLASIC were excellent predictors of ADAMTS13 deficiency, especially in patients without secondary causes.•Soluble C5b-9 levels guided management in patients with ADAMTS13 > 10%.•Our real-world data confirm that ADAMTS13, complement testing, and PLASMIC/PLASIC are valuable tools.•Our data also highlight the unmet need of using available novel prognostic tools and treatments in clinical practice.
Summary
Transplant‐associated thrombotic microangiopathy (TA‐TMA) is a complication of allogeneic transplantation (allo‐HCT). The incidence and risk factors associated with TA‐TMA are not well known. ...A retrospective analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR) was conducted including patients receiving allo‐HCT between 2008 and 2016, with the primary objective of evaluating the incidence of TA‐TMA. Secondary objectives included identification of risk factors associated with TA‐TMA, and the impact of TA‐TMA on overall survival and the need for renal replacement therapy (RRT). Among 23,665 allo‐HCT recipients, the 3‐year cumulative incidence of TA‐TMA was 3%. Variables independently‐associated with increased incidence of TA‐TMA included female sex, prior autologous transplant, primary disease (acute lymphoblastic leukaemia and severe aplastic anaemia), donor type (mismatched or unrelated donor), conditioning intensity (myeloablative), GVHD prophylaxis (sirolimus + calcineurin inhibitor), pre‐transplant kidney dysfunction and acute GVHD (time‐varying effect). TA‐TMA was associated with higher mortality (HR = 3·1, 95% Confidence Interval CI = 2·8–16·3) and RRT requirement (HR = 7·1, 95% CI = 5·7–311·6). This study provides epidemiologic data on TA‐TMA and its impact on transplant outcomes. Increased awareness of the risk factors will enable providers to be vigilant of this uncommon but serious transplant complication. The results will also provide benchmarking for future study designs and comparisons.
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