Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0035078 (renal failure)
31,970 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombotic thrombocytopenic purpura (TTP) is caused by the persistence of the highly reactive high-molecular-weight multimers of von Willebrand factor (VWF) due to deficiency of the specific VWF-cleaving protease (VWF-CP) ADAMTS13, resulting in microangiopathic disease. The acquired form is caused by autoantibodies against VWF-CP, whereas homozygous or compound heterozygous mutations of ADAMTS13 are responsible for recessively inherited TTP. We investigated 83 children with hemolytic or thrombocytopenic episodes with or without additional neurologic symptoms or renal failure. The presumed diagnosis was chronic idiopathic thrombocytopenic purpura (ITP; n = 50), TTP (n = 8), hemolytic uremic syndrome (HUS; n = 24), and Evans syndrome (n = 1). A severe deficiency of VWF-CP (< or = 5%) was found in all investigated patients with TTP and in none of those with HUS. Additionally, 2 of 50 patients with a prior diagnosis of ITP were deficient for VWF-CP. Antibodies against VWF-CP were found in 4 children. Mutation analysis of the ADAMTS13 gene in the patients deficient in VWF-CP by direct sequencing of all 29 exons identified 8 different mutations, suggesting the hereditary form of TTP in 1 patient with ITP, in the patient with Evans syndrome, and in 5 of the 8 patients with TTP. The phenotype of TTP in childhood can be rather variable. Besides the classical clinical picture, oligosymptomatic forms may occur that can delay the identification of patients at risk.
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PMID:von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. 1239 5

The significance of ADAMTS13 deficiency in adult thrombotic microangiopathy (TMA) remains controversial. In an attempt to define the characteristics of adult TMA with severe ADAMTS13 deficiency, we determined 2 groups of patients on the basis of ADAMTS13 activity (undetectable or detectable). Clinical presentation, laboratory values, autoimmune manifestations, and outcome were compared between the groups. Patients were included retrospectively from 12 centers. All fulfilled the diagnosis criteria of TMA. Patients with a history of transplantation, cancer and chemotherapy, and Centers for Disease Control and Prevention (CDC) stage C human immunodeficiency virus (HIV) infection were not included. Forty-six patients were included. Thirty-one patients had an undetectable ADAMTS13 activity (<5%), and the remaining 15 patients had ADAMTS13 activity of >25%. Severe ADAMTS13 deficiency was associated with a plasmatic inhibitor in 17 cases (55%), suggesting an immune-mediated mechanism. Patients with undetectable ADAMTS13 were more frequently of Afro-Caribbean origin than patients with detectable ADAMTS13 activity (48.4% vs 13.3%, respectively; p = 0.03). As opposed to patients with detectable ADAMTS13 activity, patients with severe ADAMTS13 deficiency displayed various autoimmune manifestations that consisted of nondestructive polyarthritis (4 cases) associated in 1 case with malar rash and extramembranous glomerulonephritis, discoid lupus (3 cases), and autoimmune endocrinopathies, Raynaud phenomenon, and sarcoidosis-like disease (1 case each). In patients with severe ADAMTS13 deficiency, antinuclear antibodies, anti-double-stranded DNA antibodies, and anticardiolipin antibodies were positive in 22 (71%) cases, 3 (9.7%) cases, and 1 (3.2%) case, respectively. One patient fulfilled the criteria for the diagnosis of systemic lupus erythematosus. During follow-up, 1 patient with severe ADAMTS13 deficiency developed antinuclear antibodies, and 3 others developed anti-double-stranded DNA antibodies, in association with neurologic manifestations and anticardiolipin antibodies in 1 case. Patients with severe ADAMTS13 deficiency also had a lower platelet count (12 x 10(9)/L; range, 2-69 x 10(9)/L) and less severe renal failure (estimated glomerular filtration rate: 78 mL/min; range, 9-157 mL/min) than patients with detectable ADAMTS13 activity (49.5 x 10(9)/L; range, 6-103 x 10(9)/L; p = 0.0004, and 15.8 mL/min; range, 5.6-80 mL/min; p < 0.0001, respectively). End-stage renal failure occurred in 1 patient with severe ADAMTS13 deficiency and in 3 patients with detectable ADAMTS13 activity (3.2% vs 21.4%, respectively; p = 0.08). Flare-up and relapse episodes and survival were comparable between the groups. Taken together, these data indicate that adult idiopathic thrombotic thrombocytopenic purpura, as defined by severe ADAMTS13 deficiency, may occur preferentially in a particular ethnic group, and is characterized by severe thrombocytopenia, mild renal involvement, and a wide spectrum of autoimmune manifestations that may be completed during follow-up. Indeed, apparently idiopathic thrombotic thrombocytopenic purpura may be considered a specific autoimmune disease.
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PMID:Severe ADAMTS13 deficiency in adult idiopathic thrombotic microangiopathies defines a subset of patients characterized by various autoimmune manifestations, lower platelet count, and mild renal involvement. 1523 11

Decreased von Willebrand factor (VWF)-cleaving protease activity (<5%) has been implicated in patients with congenital thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (Upshaw-Schulman syndrome) and associated with mutations within the ADAMTS13 gene. In this report, we describe longitudinal studies in a patient with congenital TTP who ultimately developed end-stage renal failure and required plasma therapy from infancy. The patient was deficient in plasma high molecular weight (HMW)-VWF multimers during acute disease but had increased amounts of the HMW-VWF multimers during periods of remission. DNA analysis of this patient detected homozygosity for the R692C mutation on exon 17 of the ADAMTS13 gene, previously linked to congenital TTP. The level of VWF-cleaving protease activity in the patient was remarkably low (<5%) throughout her disease, even after she entered complete remission. However, despite no improvement in the level of VWF-cleaving protease activity, this patient had complete resolution of disease following splenectomy and commencing hemodialysis, without need for ongoing plasma therapy. The patient has remained in remission for over 4 years. These observations suggest that there are other factors in conjunction with severe deficiency of VWF protease activity that participate in the platelet-mediated thrombotic complications and other disease manifestations of congenital TTP. In addition, it is possible that splenectomy could be an effective treatment option for some patients with severe, congenital TTP.
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PMID:Dissociation between the level of von Willebrand factor-cleaving protease activity and disease in a patient with congenital thrombotic thrombocytopenic purpura. 1555 Dec 80

Ticlopidine is an antiplatelet agent that interferes with platelet membrane function by inhibiting adenosine diphosphate-induced platelet activation. It is used in an increasing number of cases of cerebrovascular disease, unstable angina, coronary artery stenting, and peripheral vascular diseases. It has rare but serious adverse reactions, including thrombotic thrombocytopenic purpura (TTP). TTP is a life-threatening disease, characterized by Moschcowitz's pentad: thrombocytopenia, microangiopathic hemolytic anemia, fluctuating neurological signs, renal failure, and fever. Recent advances in elucidating the proteolytic processing of plasma von Willebrand factor (VWF) multimers have established assays for VWF-cleaving protease (VWF-CP) activity and its inhibitor(autoantibodies). These assays apparently demonstrated that TTP patients have defective enzymatic activity with or without presence of the inhibitor. VWF-CP is now identified as a metalloproteinase belonging to the ADAMTS (A Disintegrin And Metalloproteinase domain, with ThromboSpondin type 1 motif) family, termed ADAMTS13. Cases of ticlopidine-associated TTP were first reported in 1991. This complication occurs in 1 in 1600 to 1 in 5000 patients who receive ticlopidine. It is known that they develop TTP within 2 to 8 wk of starting ticlopidine treatment and show severely deficient of ADAMTS13 activity with the presence of the inhibitor. These results suggest that ticlopidine or its metabolites induce the production of autoantibodies against ADAMTS13. As treatment, discontinuation of ticlopidine therapy and rapid initiation of plasma exchange is effective: the majority of patients completely recover and relapse is uncommon. It is thus recommended that physicians should perform complete blood count every 2 weeks for 12 weeks for rapid diagnosis. Physicians and patients should be aware of this fatal but curable complication of ticlopidine therapy.
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PMID:[Clinical features and laboratory findings of thrombotic thrombocytopenic purpura associated with ticlopidine]. 1610 32

Deficiency of ADAMTS13 is found in patients with thrombotic thrombocytopenic purpura (TTP), and the genetic defects in the ADAMTS13 gene or the autoantibody against ADAMTS13 is thought to be responsible for the development of TTP. The clinical correlation and mechanisms of secondary ADAMTS13 deficiency in other disease states were investigated. In addition to TTP, ADAMTS13 levels were severely decreased in patients with sepsis-induced disseminated intravascular coagulation (DIC). The incidence of acute renal failure and serum creatinine levels in patients with ADAMTS13 activity levels lower than 20% (incidence, 41.2%; creatinine, 160 +/- 150 microM [1.81 +/- 1.70 mg/dL]) (P < .05) were significantly higher than they were in patients with ADAMTS13 activity levels higher than 20% (incidence, 15.4%; creatinine, 84 +/- 67 microM [0.95 +/- 0.76 mg/dL]) (P < .01). Additionally, unusually large von Willebrand factor multimers were detected in 26 (51.0%) of 51 patients with ADAMTS13 activity levels lower than 20%. Lower molecular weight forms of ADAMTS13 were found in the plasma of patients with sepsis-induced DIC, suggesting that the deficiency of ADAMTS13 was partially caused by its cleavage by proteases in addition to decreased synthesis in the liver. These data suggested that severe secondary ADAMTS13 deficiency can be associated with sepsis-induced DIC and may contribute to the development of renal failure.
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PMID:Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. 1618 76

The physiopathology of thrombotic thrombocytopenic purpura (TTP) has been clarified since 1998, when it was shown that TTP in adults was most often associated with an acquired deficiency of von Willebrand factor-cleaving protease (ADAMTS13) due to autoantibodies, whereas TTP in children was most often associated with a hereditary autosomal recessive severe deficiency of ADAMTS13. The hereditary form of TPP (Upshaw-Schulman syndrome) is a very rare but life-threatening disease if adequate treatment (plasma therapy) is not administered. First manifestations occur before age 10 in two thirds of cases and as soon as birth in most cases. The subsequent course is characterized by recurrent hemolytic and thrombocytopenic crises, with intervals between relapses from every 3 to 4 weeks in two thirds of cases to several months or years in one third of cases. TTP crises are associated with cerebral vascular accidents in at least 30% of patients, with a risk of neurologic sequelae in approximately 20% of patients. Renal involvement includes frequent acute renal failure due to hemoglobinuria and/or thrombotic microangiopathy during hemolytic crisis and progressive renal deterioration in approximately 50% of cases, leading to chronic or end-stage renal failure in approximately 20% of patients. The clinical phenotype may vary from the typical congenital recurrent TTP. Some mild forms are limited to a fluctuating thrombocytopenia and may be misdiagnosed as idiopathic thrombocytopenic purpura. Phenotypic variability may be observed within a single family, which suggests a role of modifier genes. Fresh frozen plasma (FFP) replaces active ADAMTS13. Ten milliliters per kilogram FFP every 2 to 4 weeks suffices to maintain remission. FFP infusions are best used preventively, given that rescue infusions may not prevent central nervous system and renal involvement. It is hoped that plasmatic or recombinant purified ADAMTS13 will be available in the years to come.
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PMID:Thrombotic thrombocytopenic purpura associated with von Willebrand factor-cleaving protease (ADAMTS13) deficiency in children. 1657 83

Thrombotic microangiopathy, which includes thrombotic thrombocytopenic purpura (TTP), shiga-toxin-associated hemolytic uremic syndrome (Stx-HUS) and atypical HUS, is characterized by the development of hyaline thrombi in the microvasculature resulting in thrombocytopenia, microangiopathic hemolysis, and organ dysfunction. Renal failure is a predominant complication of both Stx-HUS and atypical HUS, whereas neurological complications are more prominent in TTP. Other disorders such as lupus or bone marrow transplantations may occasionally present with features of thrombotic microangiopathy. Recent studies have found autoimmune inhibitors or genetic mutations of a von Willebrand factor (VWF) cleaving metalloprotease ADAMTS13 in patients with TTP. In approximately 30-50% of patients with atypical HUS, mutations have been detected in complement factor H, membrane cofactor protein (CD46), or factor I. All three proteins are involved in the regulation of complement activation. Additionally, autoantibodies of factor H have been described in patients without genetic mutations. These advances illustrate that dysregulation of VWF homeostasis or complement activation owing to genetic or autoimmune mechanisms may lead to the syndrome of thrombotic microangiopathy.
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PMID:The molecular biology of thrombotic microangiopathy. 1676 Sep 11

We encountered the case of a 4-year-old boy with thrombotic microangiopathy (TMA) of unknown etiology. Verotoxin-induced hemolytic uremic syndrome (HUS), Streptococcus-pneumoniae-related HUS, factor H deficiency, drug-induced thrombotic thrombocytopenic purpura (TTP), and ADAMTS13 (von Willebrand factor-cleaving protease; a disintegrin-like and metalloprotease with thrombospondin type 1 repeats)-related TTP were excluded. His condition was refractory to anticoagulants and plasma exchange, and his clinical course was catastrophic, with central nervous system symptoms and progressive renal failure. However, factual treatment of intravenous gamma globulin (IVIG) ended the hemolysis and resulted in a rise in platelet count. He fully recovered except for end-stage renal failure, but he underwent a successful renal transplant after peritoneal dialysis. He has not suffered a relapse of TMA or an allograft rejection for 4 years. IVIG might be an option for some patients with TMA of unknown etiology refractory to conventional treatment.
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PMID:Intravenous gamma globulin for thrombotic microangiopathy of unknown etiology. 1729 29

Haemolytic uraemic syndrome (HUS) is the primary diagnosis of 4.5% of children on chronic renal replacement therapy. Approximately 5% of all HUS cases have an "atypical" or recurrent course. Atypical HUS is an inadequate term that applies to a heterogeneous group of conditions. We describe this group as non-diarrhoeal (D-) ), non-EHEC (EHEC - ) HUS. Patients in the non-diarrhoeal, non-EHEC, relapsing group are much more likely to exhibit severe hypertension, histological findings of arterial as well as arteriolar disease, chronic and end-stage renal failure. In general, these patients have an alarmingly high risk of graft loss from disease recurrence or thrombosis ranging from 60-100%. Family history is crucial, and where family members have relapsing disease, transplantation is a very high risk procedure (recurrence 100%). Patients with (D-)HUS need very careful consideration before transplantation, including molecular investigation of complement regulators (and von Willebrandt protease (ADAMTS13) activity, although this goes beyond the scope of this review). Guidelines are accessible under http://www.espn.ucwm.ac.uk . On no account should live related donation take place unless the risks of graft loss are understood. International collaboration to identify safer ways of transplanting these challenging patients is urgently needed.
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PMID:Renal transplantation in HUS patients with disorders of complement regulation. 1705 51

Hemolytic uremic syndrome (HUS) is the consequence of platelet consumption at sites of endothelial injury. Perinatal asphyxia (PA) may cause renal failure after birth and can be associated with disseminated intravascular coagulopathy (DIC) with platelet consumption. No biological investigation permits us to distinguish clearly between neonatal HUS and DIC. We report on three neonates with renal failure due to different degrees of PA. They presented biological features compatible with HUS, such as fragmentocytes ( approximately 2%), thrombopenia (<50,000/mm(3)), and anemia (<8 g/dl). One patient required peritoneal dialysis. Haptoglobin was undetectable for all three patients. Factor H and factor I, as well as components of the complement system (C3 and C4) and ADAMTS13 activity, were decreased. Two patients received daily fresh frozen plasma infusions over the first 4 weeks. Renal function improved in two patients; one patient had chronic renal failure. No neurological sequelae were noted. All blood parameters suggestive of thrombotic microangiopathy (TMA) were normal on days 12, 30, and 60. We hypothesize that endothelial cell damage concomitant with PA may lead to a vicious circle that results in consumption of platelets and plasma factors involved in hemostasis and/or fibrinolysis. In conclusion, PA, DIC and HUS are difficult to distinguish, and endothelial cell damage may be their common pathophysiological pathway.
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PMID:Perinatal asphyxia may present with features of neonatal atypical hemolytic uremic syndrome. 1767 53


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