How I treat: the clinical differentiation and initial treatment of adult patients with atypical hemolytic uremic syndrome.

Published data demonstrating the efficacy of complement inhibition therapy in patients with atypical hemolytic uremic syndrome (aHUS) are remarkable in contrast to the historically poor long-term prognosis for aHUS patients treated with plasma-based therapy. Although both aHUS and acquired thrombotic thrombocytopenic purpura (TTP) remain clinical diagnoses, an increased understanding of both conditions has improved our ability to differentiate aHUS from acquired TTP. These same data have also demonstrated the importance of a more rapid identification and diagnosis of aHUS as the recovery of end-organ injury present appears to be related to the time to initiate therapy with eculizumab. The diagnosis of acquired TTP can be confirmed by the finding of severely deficient ADAMTS13 activity (<10%) with evidence of an ADAMTS13 antibody inhibitor whereas merely deficient ADAMTS13 activity in the absence of an ADAMTS13 autoantibody is more consistent with congenital TTP. In the absence of an objective diagnostic test, clinicians must rely collectively on platelet count, serum creatinine, and ADAMTS13 activity in the context of the response to plasma exchange therapy to identify patients whose diagnosis is most consistent with aHUS, and thus be more likely to benefit from therapy with eculizumab.

Pathophysiology and treatment of typical and atypical hemolytic uremic syndrome.

Hemolytic uremic syndrome is a rare disease, frequently responsible for renal insufficiency in children. Recent findings have led to renewed interest in this pathology. The discovery of new gene mutations in the atypical form of HUS and the experimental data suggesting the involvement of the complement pathway in the typical form, open new perspectives for treatment. This review summarizes the current state of knowledge on both typical and atypical hemolytic uremic syndrome pathophysiology and examines new perspectives for treatment.

Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom.

Atypical haemolytic uraemic syndrome (aHUS) is associated with a poor prognosis with regard to survival at presentation, recovery of renal function and transplantation. It is now established that aHUS is a disease of complement dysregulation with mutations in the genes encoding both complement regulators and activators, and autoantibodies against the complement regulator factor H. Identification of the underlying molecular abnormality in an individual patient can now help to guide their future management. In these guidelines we make recommendations for the investigation and management of aHUS patients both at presentation and in the long-term. We particularly address the role of renal transplantation alone and combined liver-kidney transplantation.

Anti-Factor H autoantibodies in a fifth renal transplant recipient with atypical hemolytic and uremic syndrome.

Hemolytic uremic syndrome (HUS) associated with anti-Factor H (anti-FH) autoantibodies is a recently described pathophysiological entity. Monitoring of anti-FH IgG titer may be a sensitive marker of disease activity and guide treatment to eliminate circulating anti-FH antibodies. We report here a case of atypical HUS (aHUS) in which anti-FH autoantibodies were detected during the course of a fifth kidney transplant, 30 years after the first flare of aHUS. This exceptional case suggests that early, specific management based on immunosuppressive therapy and plasma exchanges monitored by anti-FH IgG titer may result in long-term graft survival.

TTP/HUS and prognosis: the syndrome and the disease(s).

Patients presenting with the syndrome of microangiopathic hemolysis and thrombocytopenia, without Shiga toxin-associated colitis, have thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). Prognosis for TTP/HUS has changed over time from a fatal disorder associated with the classic pentad to a syndrome associated with 80% survival in the plasma exchange era. A growing number of mechanisms, including but not exclusive to severe ADAMTS13 deficiency, are now understood to result in this syndrome, and the prognosis of patients with TTP/HUS is related to many additional factors. This update on prognosis explores recent registry data studying both acquired idiopathic and also familial or recurrent forms of TTP/HUS, to delineate how mortality varies by underlying disease mechanism. This paper also explores the association between mortality and clinical presenting features, as well as whether the case is a primary or relapsed presentation. Recent data support an understanding of TTP/HUS as a heterogeneous syndrome with variable mortality, and with specific subgroups demonstrating an excellent outcome.

The thrombotic thrombocytopenic purpura and hemolytic uremic syndromes: overview of pathogenesis (Experience of The Oklahoma TTP-HUS Registry, 1989-2007).

The Oklahoma TTP (thrombotic thrombocytopenic purpura)-HUS (hemolytic uremic syndrome) Registry, an inception cohort of 382 consecutive patients with TTP-HUS, provides a complete community perspective of these syndromes. TTP is the diagnostic term used for all adults, with or without neurologic or renal abnormalities; it is typically an acquired disorder; it may rarely result from congenital ADAMTS13 deficiency. HUS is the term used for children who have renal failure, most often caused by Escherichia coli O157:H7 infection; it may rarely result from congenital abnormalities of complement regulation. Clinical categories related to associated conditions and potential etiologies provide a structure for describing pathogenesis of the acquired syndromes. (1) Following allogeneic hematopoietic stem cell transplantation; a disorder primarily affecting kidneys described as transplantation-associated thrombotic microangiopathy. (2) Pregnancy-associated; pregnancy is a prominent risk factor for the development of TTP. (3) Drug-associated; acute, immune-mediated systemic syndromes and also dose-dependent renal toxicity. (4) Bloody diarrhea prodrome, suggesting an enteric infectious etiology. (5) Presence of an additional autoimmune disorder. (6) Idiopathic. A severe deficiency of ADAMTS13 activity contributes to the pathogenesis of many idiopathic patients and also some patients who present during pregnancy, with bloody diarrhea, or who have additional autoimmune disorders.

The Oklahoma Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome Registry: the Swiss connection.

OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) was initially described as an uncommon and usually fatal disorder. With effective treatment it is more frequently diagnosed, the clinical presentations are more diverse, and long-term sequelae are becoming recognized. METHODS: Patient data are from The Oklahoma TTP-hemolytic uremic syndrome (HUS) Registry, an inception cohort of 348 consecutive patients with their first episode of clinically diagnosed TTP or HUS, 1989-2006. The Registry enrolls all patients in a defined region who are diagnosed with TTP or HUS and for whom plasma exchange treatment is requested. ADAMTS13 activity has been analyzed on 235 (93%) of 254 patients since 1995 at the University of Berne, Switzerland. Patients are described by clinical categories, related to their associated conditions and clinically apparent etiologies, and by the presence of severe ADAMTS13 deficiency. RESULTS AND CONCLUSIONS: The clinical spectrum of syndromes described as TTP is variable with multiple etiologies. Advances in clinical and laboratory investigation have provided better understanding of the pathogenesis of these syndromes, their clinical evaluation and management, and their long-term outcomes. In addition to new information about TTP, these studies provide a model for translational research to define the complete community spectrum of uncommon disorders.

What's new in haemolytic uraemic syndrome?

Recent advances in understanding the aetiology of the disorders that make up the haemolytic uraemic syndrome (HUS) permit a revised classification of the syndrome. With appropriate laboratory support, an aetiologically-based subgroup diagnosis can be made in all but a few cases. HUS caused by enterohaemorrhagic Escherichia coli remains by far the most prevalent subgroup, and new insights into this zoonosis are discussed. The most rapidly expanding area of interest is the subgroup of inherited and acquired abnormalities of complement regulation. Details of the pathogenesis are incomplete but it is reasonable to conclude that local activation of the alternative pathway of complement in the glomerulus is a central event. There is no evidence-based treatment for this diagnostic subgroup. However, in circumstances where there is a mutated plasma factor such as complement factor H, strategies to replace the abnormal protein by plasmapheresis or more radically by liver transplantation are logical, and anecdotal successes are reported. In summary, the clinical presentation of HUS gives a strong indication as to the underlying cause. Patients without evidence of EHEC infection should be fully investigated to determine the aetiology. Where complement abnormalities are suspected there is a strong argument for empirical and early plasma exchange, although rapid advances in this field may provide more specific treatments in the near future.

Where next with atypical hemolytic uremic syndrome?

Hemolytic uremic syndrome (HUS) is a systemic disease characterized by damage to endothelial cells, erythrocytes and kidney glomeruli. A "typical" form of HUS follows gastrointestinal infection with enterohemorrhagic E. coli (e.g. O157:H7). Atypical HUS (aHUS) is not associated with gastrointestinal infections but is sporadic or familial in nature. Approximately 50% of aHUS cases are associated with a mutation in one or more genes coding for proteins involved in regulation or activation of the alternative pathway of complement. The link between the disease and the mutations shows the important balance of the alternative pathway between activation and regulation on host cell surfaces. It also demonstrates the power of this pathway in destroying cellular targets in general. In this review we discuss the current knowledge on pathogenesis, classification, diagnostics and management of this disease. We indicate a comprehensive diagnostic approach for aHUS based on the latest knowledge on complement dysregulation to gain both immediate and future patient benefit by assisting in choosing more appropriate therapy for each patient. We also indicate directions in which therapy of aHUS might improve and indicate the need to re-think the terminology and categorisation of the HUS-like diseases so that any advantage in the understanding of complement regulatory problems can be applied to patients accurately.

Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome.

The hemolytic uremic syndrome is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. There are two general types. One occurs in epidemic form and is diarrheal associated (D+HUS). It has a good prognosis. The second is a rare form known as atypical (aHUS), which may be familial or sporadic, and has a poor prognosis. aHUS is increasingly recognized to be a disease of defective complement regulation, particularly cofactor activity. Mutations in membrane cofactor protein (MCP; CD46) that predispose to the development of aHUS were first identified in 2003. MCP is a membrane-bound complement regulator that acts as a cofactor for the factor I-mediated cleavage of C3b and C4b deposited on host cells. More than 20 different mutations in MCP have now been identified in patients with aHUS. Many of these mutants have been functionally characterized and have helped to define the pathogenic mechanisms leading to aHUS development. Over 75% of the reported mutations cause a reduction in MCP expression, due to homozygous, compound heterozygous or heterozygous mutations. This deficiency of MCP leads to inadequate control of complement activation on endothelial cells after an initiating injury. The remaining MCP mutants are expressed, but demonstrate reduced ligand (C3b/C4b) binding capacity and cofactor activity of MCP. MCP mutations in aHUS demonstrate incomplete penetrance, indicating that additional genetic and environmental factors are required to manifest disease. MCP mutants as a cause of aHUS have a favorable clinical outcome in comparison to patients with factor H (CFH) or factor I (IF) mutations. In 90% of the renal transplants performed in patients with MCP-HUS, there has been no recurrence of the primary disease, whilst >50% of factor I or factor H deficient patients have had a prompt recurrence. This highlights the importance of defining and characterizing the underlying genetic defects in patients with aHUS.

[Haemolytic uremic syndrome and thrombotic thrombocytopenic purpura: classification based on molecular etiology and review of recent developments in diagnostics]. / A hemolitikus urémiás szindróma és a trombotikus thrombocytopeniás purpura molekuláris szemléletu klasszifikációja és diagnosztikájuknak aktuális kérdései.

Haemolytic uremic syndrome and thrombotic thrombocytopenic purpura are overlapping clinical entities based on historical classification. Recent developments in the unfolding of the pathomechanisms of these diseases resulted in the creation of a molecular etiology-based classification. Understanding of some causative relationships yielded detailed diagnostic approaches, novel therapeutic options and thorough prognostic assortment of the patients. Although haemolytic uremic syndrome and thrombotic thrombocytopenic purpura are rare diseases with poor prognosis, the precise molecular etiology-based diagnosis might properly direct the therapy of the affected patients. The current review focuses on the theoretical background and detailed description of the available diagnostic possibilities, and some practical information necessary for the interpretation of their results.

[The clinical course and long-term outcome of hemolytic-uremic syndrome in children]. / Vaiku hemolizinio ureminio sindromo klinikine eiga ir velyvosios baigtys.

The aim of this study was to evaluate the long-term outcome of hemolytic-uremic syndrome in children and the dependence of outcome on severity of the acute phase of the illness. We analyzed data of 20 children who were hospitalized and treated at the Clinic of Children's Diseases, Kaunas University of Medicine Hospital, during 1995-2006. Data were obtained from case histories and outpatient case records with the help of prepared questionnaire. The course of acute disease and health status were evaluated at discharge from hospital and at 6-month, 1-year, and 3-year follow-ups. There were 8 boys and 12 girls in the study group; their age ranged from 3 months to 12 years. According to the clinical course of the acute phase of the illness, children were divided into two groups. Group A (severe course) consisted of 15 patients with blood leucocytosis (more than 20x10(9)/L) and signs of CNS involvement, who required renal replacement therapy. Group B (mild course) consisted of five children who did not have such symptoms. Twelve (60%) children underwent dialysis during acute illness; two patients died (10%). One (20%) patient in Group B had proteinuria, four (80%) had renal insufficiency, and three (60%) had arterial hypertension at discharge from hospital. Subsequently these changes disappeared, and 3 years later arterial hypertension was detected in 1 (25%) patient in Group B. Eight (61.5%) patients from Group A had renal insufficiency, nine (69.2%) had proteinuria, and two (15.4 %) had arterial hypertension at discharge from hospital. Three years later from the onset of the disease, two (20%) patients had arterial hypertension, proteinuria was detected in two (20%) patients, and renal insufficiency remained in six (60%) children. Our data revealed that the outcomes of the disease are strongly influenced by the severity of the acute phase of the illness.

Outcome of severe adult thrombotic microangiopathies in the intensive care unit.

OBJECTIVE: Thrombotic microangiopathies, namely thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, are uncommon microvascular occlusive diseases. Despite the dramatic improvement in the outcome by exogenous plasma supply, either through plasma infusion or through plasma exchange, patients frequently require support in the intensive care unit. In the present study, we evaluated the outcome of a large cohort of patients with severe thrombotic microangiopathies. DESIGN: A retrospective multicenter study from January 1998 to June 2001. SETTING: Fourteen French university hospital medical intensive care units. PATIENTS: Sixty three adult patients with severe thrombotic microangiopathies. MEASUREMENTS AND RESULTS: Of the 63 patients, 19 had a clinical presentation of thrombotic thrombocytopenic purpura, 18 had hemolytic uremic syndrome and 26 had combined neurologic and renal failures. Infections were the main etiology associated with thrombotic microangiopathies. The mortality rate was 35%. Of the survivors, all achieved complete remission. Whereas neurologic failure assessed through the Glasgow coma scale was an independent predictor of mortality [HR=0.845 (CI 95%: 0.759-0.940), P=0.002], renal impairment did not appear to be an adverse prognostic factor. The use of plasma exchange was independently associated with survival [HR=0.269 (CI 95%: 0.104-0.691), P=0.006]. CONCLUSIONS: Thrombotic microangiopathies with severe organ dysfunctions leading to hospitalization in the intensive care unit are associated with high mortality. Neurologic impairment appears to be the main adverse prognostic factor correlated to mortality, and the study confirms the importance of plasma exchange in the treatment of high-risk patients.

Adult hemolytic-uremic syndrome. A review of 37 cases.

BACKGROUND: Adult hemolytic-uremic syndrome is a serious, poorly understood disease with a high and variable mortality. We studied several demographic, clinical, and treatment variables, related them to outcome, and developed a new classification. METHODS: We analyzed data from 37 patients admitted from 1981 to 1991 who fulfilled four criteria (age > 16 years, microangiopathic hemolytic anemia, creatinine level > 150 mumol/L [> 1.7 mg/dL], and no artificial heart valve). Three outcome variables were studied (survival vs death, recurrence vs no recurrence, and chronic renal failure vs no chronic renal failure). RESULTS: Eleven (30%) of the patients died, 10 (27%) needed dialysis, five (14%) developed chronic renal failure, and nine (24%) had recurrent episodes. Patients who presented with colitis did not die or have recurrences, but they developed chronic renal failure as often as other patients. Patients with hemolytic-uremic syndrome secondary to other diseases had the worst survival and the most recurrences. Those without any triggering factor (primary cases) were in between. In multivariate analysis, hemolytic-uremic syndrome secondary to colitis, a higher white blood cell count at admission, and a high maximum mean arterial pressure were associated with good survival prognosis. CONCLUSIONS: The persistence of the trigger of adult hemolytic-uremic syndrome sets the stage for outcome. If the trigger is transient (such as Escherichia coli colitis), the disease will not recur and is rarely lethal. If no trigger is apparent (primary hemolytic-uremic syndrome) or the trigger persists (systemic lupus erythematosus and cancer), the syndrome has a high mortality and often recurs. We suggest a new classification: (1) extrinsic hemolytic-uremic syndrome: (a) toxic, (b) infectious; (2) intrinsic hemolytic-uremic syndrome: (a) primary, (b) secondary. The use of this classification, combined with simple data obtained at presentation and a further division of the cause as transient or persistent and irreversible, may improve the selection of therapy.

Haemolytic uraemic syndrome: a review.

OBJECTIVES: To provide an overview of the current understanding of the classification of haemolytic uraemic syndrome (HUS) and to describe the epidemiology, pathogenesis, clinical picture, renal histopathological findings, treatment and prevention of shiga toxin (Stx)-associated HUS, the most common type of HUS and; to compare and contrast features of idiopathic (atypical) HUS and inherited HUS with those of Stx-associated HUS. DATA SOURCE: A literature review was performed of major published series between 1989 and 1998 inclusive, using the Index Medicus and MEDLINE search. Some earlier published series were also reviewed in instances where they indirectly led to the current studies or reported on rarer organ involvements in HUS. STUDY SELECTION: Data and opinions from twelve general reviews of HUS, twelve on aetiology and classification, twelve on clinical features, eight on pathogenesis and nine on treatment and prognosis are summarised. CONCLUSION: HUS is a thrombotic microangiopathy with several aetiologies currently thought to play a role. Vascular endothelial cell injury appears to be central to the pathogenesis of all forms of HUS, although the triggering factors may be different and not well understood in some cases. In HUS, supportive therapy is of paramount importance. Reported specific therapies do not have sufficient evidence to support them. Prevention of HUS is possible in Stx-associated form, but not in the others. In patients who go on to develop end-stage renal failure, transplantation is possible, but recurrence rates are high in forms other than those which are Stx-associated. Persisting sequelae in other organs in HUS are infrequent.

Diagnosis and classification of hemolytic uremic syndrome: the Hungarian experience.

BACKGROUND: Hemolytic uremic syndrome (HUS) is a rare disease with various etiologies, making the identification of the specific forms and appropriate treatment difficult. Therefore, clinical and laboratory data from these patients need to be analyzed in national and international registries. Herein we have described 47 Hungarian HUS patients with detailed laboratory and clinical data obtained between 2008 and 2010. METHODS: Blood samples and clinical data of 47 patients with HUS diagnosed according to characteristic clinical signs were submitted for diagnostic evaluation, including complement protein and genetic analysis, measurement of ADAMTS13 activity and antibody analysis against O157LPS and factor H. RESULTS: There were 8 patients with typical diarrhea-positive HUS; 13 with atypical HUS (aHUS) and 26 with secondary HUS/thrombotic thrombocytopenic purpura group characterized by signs of complement consumption and decreased ADAMTS13 activity. Thus, decreased total alternative pathway activity is a promising diagnostic parameter with good sensitivity for aHUS. CONCLUSIONS: These observations highlight the requirement for multiple diagnostic tests together with clinical data to identify the specific cause of HUS. Because the long-term prognosis of aHUS, eg, graft survival after renal transplantation, may vary according to the molecular etiology, it is important for all affected patients to undergo a detailed molecular diagnosis of the disease. There is a clear clinical need for the development and application of novel assay in this field to allow more rapid efficient diagnosis of patients who undergo a first episode of HUS.