Haemolytic-uremic syndrome due to infection with adenovirus: A case report and literature review.

RATIONALE: Haemolytic-uremic syndrome is a rare but serious complication of bacterial and viral infections, which is characterized by the triad of: acute renal failure, microangiopathic haemolytic anemia and thrombocytopenia, sometimes severe, requiring peritoneal dialysis. In Europe, hemolytic-uremic syndrome (HUS) in paediatric pathology is primarily caused by Shiga toxin-producing Escherichia coli (STEC) O157, followed by O26. Beside these etiologies, there are other bacterial and viral infections, and also noninfectious ones that have been associated to lead to HUS as well: in the progression of neoplasia, medication-related, post-transplantation, during pregnancy or associated with the antiphospholipid syndrome, systemic lupus erythematosus or family causes with autosomal dominant or recessive inheritance. In terms of pathogenesis, HUS is the result of endothelial injury, most commonly being a result of the action of Shiga toxin. The unfavorable prognosis factors being represented by the age of more than 5 years old, different etiologies from STEC, persistent oligoanuria, central nervous system and glomerular impairment, the association of fever with leukocytosis. HUS is responsible for 7% of cases of hypertension in infants, and an important cause of significant kidney damage in adults. PATIENT CONCERNS: We present one case of HUS caused by adenovirus in a boy of 1 year and 7 months old with severe evolution, which required peritoneal dialysis. DIAGNOSE: Stool sample repeated examination for adenovirus antigen was positive in 2 samples. INTERVENTION: During hospitalization, the patient required 8 peritoneal dialysis sessions. OUTCOME: The renal function was corrected on discharge, the patient required cardiovascular monitoring 1 month after discharge. LESSON: Although the most common cause that leads to HUS remains STEC, other etiologies like viral ones that may be responsible for severe enteric infection with progression into HUS should not be neglected.

Treatment of Acute Kidney Injury in Hemolythic Uremic Syndrome (TTP).

INTRODUCTION: Plasmapheresis is often used as a therapy in the treatment of thrombotic thrombocytopenic purpura (TTP). TTP is manifested in thrombotic microangiopathy, consumed thrombocytopenia, hemolytic anemia and acute kidney injury with HUS development, neurologic dysfunction, and fever. CASE REPORT: we will present a case of a patient with acute kidney injury and refractory TTP at the beginning of hospitalization, subsequently manifested in secondary nephrotic syndrome. The patient was a female, 39 years of age, who as an emergency case was referred from the hospital in East Sarajevo to the Clinic of Endocrinology, Diabetes and Metabolism Disorders of the Clinical Center University of Sarajevo with suspected TTP. A few days before hospitalization she had a fever and vomiting, and therefore consulted her physician. She was hospitalized due to severe general condition, generalized edema, visible body hematomas, and diuresis amounting to 600 ml/12 hours. Laboratory results on admission were as follows: Leukocytes 19.5, Erythrocytes 3.23, Hemoglobin 103, Hematocrit 28.8%, Platelets 65.4 with few schistocytes and 2 reticulocytes, Sodium 140 mmol/L,, Potassium 4.5 mmol/L, Calcium 1.90 mmol/L, Glucose 7.9 mmol/L, Urea 37.5 mmol/L, Creatinine 366 umol/L,, Bilirubin 19.0 umol/L, Lactate dehydrogenase 1194 U /L. The patient was communicative, in cardiopulmonary sufficient state. Central venous catheter was placed in the right jugular vein and the first plasmapheresis was performed. During the hospitalization 38 plasmapheresis treatments with frozen plasma were performed, followed by three Rituximab treatment cycles. After the last plasmapheresis treatment a platelet count was 138. Also, parameters of the renal function were in their referent values. At the beginning of the treatment proteinuria was 19.6 g/24 hours urine. We were faced with a dilemma whether renal biopsy should be repeated in the future given that it might be the case of primary and not secondary nephrotic syndrome. Controlled proteinuria was 4.7g after plasmapheresis. The patient used only Prednisolone at a dose of 10 mg daily and although initially diagnosed with acute kidney injury she was not treated with dialysis. CONCLUSION: early diagnosis and early start of plasmapheresis therapy is vital for treatment of patients with acute kidney injury and TTP (HUS). A small number of patients is refractory to plasmapheresis and introducing Rituximab and plasmapheresis treatment is recommended.

Renal thrombotic microangiopathy in patients with cblC defect: review of an under-recognized entity.

Methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type, is the most common genetic type of functional cobalamin (vitamin B12) deficiency. This metabolic disease is characterized by marked heterogeneity of neurocognitive disease (microcephaly, seizures, developmental delay, ataxia, hypotonia) and variable extracentral nervous system involvement (failure to thrive, cardiovascular, renal, ocular) manifesting predominantly early in life, sometimes during gestation. To enhance awareness and understanding of renal disease associated with cblC defect, we studied biochemical, genetic, clinical, and histopathological data from 36 patients. Consistent clinical chemistry features of renal disease were intravascular hemolysis, hematuria, and proteinuria in all patients, with nephrotic-range proteinuria observed in three. Renal function ranged from normal to renal failure, with eight patients requiring (intermittent) dialysis. Two thirds were diagnosed with atypical (diarrhea-negative) hemolytic uremic syndrome (HUS). Renal histopathology analyses of biopsy samples from 16 patients revealed glomerular lesions typical of thrombotic microangiopathy (TMA). Treatment with hydroxycobalamin improved renal function in the majority, including three in whom dialysis could be withdrawn. Neurological sequelae were observed in 44 % and cardiopulmonary involvement in 39 % of patients, with half of the latter group demonstrating pulmonary hypertension. Mortality reached 100 % in untreated patients and 79 and 56 % in those with cardiopulmonary or neurological involvement, respectively. In all patients presenting with unclear intravascular hemolysis, hematuria, and proteinuria, cblC defect should be ruled out by determination of blood/plasma homocysteine levels and/or genetic testing, irrespective of actual renal function and neurological status, to ensure timely diagnosis and treatment.

Defining the role of pneumococcal neuraminidases and O-glycosidase in pneumococcal haemolytic uraemic syndrome.

The host and bacterial factors that lead to development of pneumococcal haemolytic uraemic syndrome (pHUS) remain poorly defined; however, it is widely believed that pneumococcal exposure of the Thomsen-Friedenreich antigen (T-antigen) on host surfaces is a key step in pathogenesis. Two enzymatic activities encoded by pneumococci determine the level of T-antigen exposed. Neuraminidases cleave terminal sialic acid to expose the T-antigen which is subsequently cleaved by O-glycosidase Eng. While a handful of studies have examined the role of neuraminidases in T-antigen exposure, no studies have addressed the potential role of O-glycosidase. This study used 29 pHUS isolates from the USA and 31 serotype-matched controls. All isolates contained eng, and no significant correlation between enzymatic activity and disease state (pHUS and blood non-pHUS isolates) was observed. A prior study from Taiwan suggested that neuraminidase NanC contributes to the development of pHUS. However, we observed no difference in nanC distribution. Similar to previously published data, we found no significant correlation between neuraminidase activity and disease state. Accurate quantification of these enzymatic activities from bacteria grown in whole blood is currently impossible, but we confirmed that there were no significant correlations between disease state and neuraminidase and O-glycosidase transcript levels after incubation in blood. Genomic sequencing of six pHUS isolates did not identify any genetic elements possibly contributing to haemolytic uraemic syndrome. These findings support the hypothesis that while exposure of T-antigen may be an important step in disease pathogenesis, host factors likely play a substantial role in determining which individuals develop haemolytic uraemic syndrome after pneumococcal invasive disease.

Averting the Legacy of Kidney Disease - Focus on Childhood.

World Kidney Day 2016 focuses on kidney disease in childhood and the antecedents of adult kidney disease that can begin in earliest childhood. Chronic kidney disease (CKD) in childhood differs from that in adults, as the largest diagnostic group among children includes congenital anomalies and inherited disorders, with glomerulopathies and kidney disease in the setting of diabetes being relatively uncommon. In addition, many children with acute kidney injury will ultimately develop sequelae that may lead to hypertension and CKD in later childhood or in adult life. Children born early or who are small-for date newborns have relatively increased risk for the development of CKD later in life. Persons with a high-risk birth and early childhood history should be watched closely in order to help detect early signs of kidney disease in time to provide effective prevention or treatment. Successful therapy is feasible for advanced CKD in childhood; there is evidence that children fare better than adults, if they receive kidney replacement therapy including dialysis and transplantation, while only a minority of children may require this ultimate intervention. Because there are disparities in access to care, effort is needed so that those children with kidney disease, wherever they live, may be treated effectively, irrespective of their geographic or economic circumstances. Our hope is that World Kidney Day will inform the general public, policy makers and caregivers about the needs and possibilities surrounding kidney disease in childhood.

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.

Microalbuminuria en pacientes pediátricos con diagnóstico de síndrome hemolítico urémico / Microalbuminuria in pediatric patients diagnosed with hemolytic uremic syndrome

Introducción: El síndrome hemolítico urémico (SHU) se caracteriza por la presencia de anemia hemolítica microangiopática, trombocitopenia y afectación renal aguda. Es la principal causa de falla renal aguda en niños menores de 3 años. Un número variable de pacientes evoluciona con afectación renal a largo plazo con proteinuria, hipertensión arterial e insuficiencia renal crónica. Objetivo: Evaluar la afectación renal mediante el índice microalbuminuria/creatininuria en pacientes pediátricos con diagnóstico de SHU. Pacientes y Método: Estudio descriptivo de cohorte concurrente que analizó la presencia de microalbuminuria en pacientes diagnosticados de SHU entre enero de 2001 y marzo de 2012, que evolucionaron sin hipertensión y con función renal normal (clearance mayor de 90 ml/min medido por fórmula de Schwartz). Se evaluaron factores demográficos (edad, sexo), presentación clínica en el momento del diagnóstico, uso de antibióticos previo al ingreso y requerimiento de terapia de reemplazo renal. Resultados: Se estudiaron 24 pacientes, el 54% varones; la edad promedio en el momento del diagnóstico fue de 2 años; un 45% requirió diálisis peritoneal; un 33% evolucionó con microalbuminuria persistente; cuatro pacientes recibieron tratamiento antiproteinúrico con buena respuesta. El promedio de seguimiento fue de 6 años (rango: 6 meses a 11 años); todos los pacientes durante el seguimiento evolucionaron con creatinina plasmática normal. Conclusiones: En nuestro grupo, el porcentaje de microalbuminuria persistente en pacientes con diagnóstico previo de SHU fue similiar a lo descrito en la literatura; el tratamiento con antiproteinúricos podría retrasar el daño renal, pero es necesario realizar estudios prospectivos multicéntricos.

Introduction: Hemolytic uremic syndrome (HUS) is characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney failure. It is the leading cause of acute kidney failure in children under 3 years of age. A variable number of patients develop proteinuria, hypertension, and chronic renal failure. Objective: To evaluate the renal involvement in pediatric patients diagnosed with HUS using the microalbumin/creatinine ratio. Patients and Methods: Descriptive concurrent cohort study that analyzed the presence of microalbuminuria in patients diagnosed with HUS between January 2001 and March 2012, who evolved without hypertension and normal renal function (clearance greater than 90 ml/min using Schwartz formula). Demographic factors (age, sex), clinical presentation at time of diagnosis, use of antibiotics prior to admission, and need for renal replacement therapy were evaluated. Results: Of the 24 patients studied, 54% were male. The mean age at diagnosis was two years. Peritoneal dialysis was required in 45%, and 33% developed persistent microalbuminuria. Antiproteinuric treatment was introduce in 4 patients, with good response. The mean follow-up was 6 years (range 6 months to 11 years). The serum creatinine returned to normal in all patients during follow up. Conclusions: The percentage of persistent microalbuminuria found in patients with a previous diagnosis of HUS was similar in our group to that described in the literature. Antiproteinuric treatment could delay kidney damage, but further multicenter prospective studies are necessary.

Insights from the use in clinical practice of eculizumab in adult patients with atypical hemolytic uremic syndrome affecting the native kidneys: an analysis of 19 cases.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a devastating form of renal thrombotic microangiopathy. Despite plasma exchange, the standard treatment of aHUS for decades, the renal prognosis for patients with aHUS has remained poor. We assessed the off-trial use of eculizumab in adult patients with aHUS affecting the native kidneys. STUDY DESIGN: A retrospective study was conducted. aHUS was defined as the presence of 3 or more of the following: acute kidney injury (serum creatinine >1.4 mg/dL [120 µmol/L]), mechanical hemolytic anemia, thrombocytopenia, and the presence of thrombotic microangiopathy features in a kidney biopsy specimen. Patients who had received 4 or more weekly 900-mg infusions of eculizumab were included. SETTING & PARTICIPANTS: 19 patients were identified through a query sent to all French nephrology centers. OUTCOMES & MEASUREMENTS: Evolution of kidney function, hemolysis, and thrombocytopenia after the initiation of eculizumab therapy. RESULTS: All patients had acute kidney injury (serum creatinine range, 2.2-17.0 mg/dL) and 12 required hemodialysis. Thirteen patients carried a mutation in 1 complement gene and 1 had anti-factor H antibodies. For first-line therapy, 16 patients underwent plasma exchange and 3 patients received eculizumab. Median time between aHUS onset and eculizumab therapy initiation was 6 (range, 1-60) days and median time to platelet count normalization after eculizumab therapy initiation was 6 (range, 2-42) days. At the 3-month follow-up, 4 patients still required dialysis, 8 had non-dialysis-dependent chronic kidney disease, and 7 had normalized kidney function. At last follow-up (range, 4-22 months), 3 patients remained dialysis dependent, 7 had non-dialysis-dependent chronic kidney disease (estimated glomerular filtration rate, 17-55 mL/min/1.73 m(2)), and 9 had normal kidney function. Risks of reaching end-stage renal disease within 3 months and 1 year of aHUS onset were reduced by half in eculizumab-treated patients compared with recent historical controls. LIMITATIONS: Retrospective study and use of historical controls. CONCLUSIONS: Our data indicate that eculizumab improves kidney disease outcome in patients with aHUS.

Case series: hemolytic uremic syndrome--another cause of transplant dysfunction.

BACKGROUND: Renal transplantation is the optimal treatment for suitable patients with end-stage renal disease (ESRD). However, acute graft dysfunction occurs in 5%-35% of patients. This is commonly due to acute rejection, drug toxicity, ureteric obstruction, or infection. Atypical hemolytic uremic syndrome (aHUS), either recurrent or de novo, is uncommon after transplantation. CASES: We highlight three cases of acute transplant dysfunction in which transplant biopsy revealed HUS without associated clinical or hematologic clues to the etiology. Two cases had recurrent HUS and 1 had de novo HUS secondary to tacrolimus therapy. Screenings for ADAMTS-13 and gene mutations of complement regulatory proteins were negative. Thrombocytopenia and red blood cell fragments on blood film appeared some days later. TREATMENT: Treatment comprised a combination of plasma exchange with fresh-frozen plasma and switching immunosuppressive therapy, which led to the recovery of the above hematologic features but salvaged graft function in only 1 case. CONCLUSIONS: Classical hematologic findings of HUS appeared late in these cases. HUS should be considered in cases of allograft dysfunction where there is no obvious cause, and biopsy should be performed. This enables early initiation of therapy to gain rapid recovery of hematologic parameters and potentially of transplant function.

Diagnosis of Streptococcus pneumoniae-associated hemolytic uremic syndrome.

BACKGROUND: Hemolytic uremic syndrome related to pneumococcal infection (P+HUS) can be difficult to diagnose due to the lack of a specific test and the absence of a consensus for definite diagnostic criteria. METHODS: A retrospective study was conducted on the cases that have been considered as P+HUS in the participating centers during the past 10 years. Diagnostic strategy and criteria used for the diagnosis of P+HUS were evaluated and compared with a review of literature data. RESULTS: A total of 17 children were studied. Tests ruling out other causes of HUS were performed in 94% of cases. Direct confirmatory tests for P+HUS were done in a minority of cases as Thomsen-Friedenreich antigen testing using lectin assay were done in only 2 patients (11%). Retrospectively, the diagnosis of P+HUS was confirmed in 28% to 89% of cases depending on the already published criteria used. A literature review focused on the last 15 years confirmed these diagnostic difficulties due to variable definition criteria and bring a new light on the potential usefulness of tests used to reveal T activation in this setting. CONCLUSION: To date, in a context of suspicion of P+HUS, no precise, practical and consensual strategy exists for T-antigen exposure diagnosis. The T-antigen activation test using peanut lectin might be the most appropriate test for a direct diagnosis of P+HUS. A large prospective study is required to confirm this hypothesis. However, before such data are available, its use could be of help when a suspicion of P+HUS is present given the therapeutic impact of such a diagnosis.

Neonatal atypical hemolytic uremic syndrome due to methylmalonic aciduria and homocystinuria.

BACKGROUND: Inborn errors of cobalamin (Cbl) absorption and metabolism form a large group of rare diseases that include Cbl-C disorder. Among the renal complications of Cbl-C disorder, atypical hemolytic uremic syndrome (HUS) is the least common and has been described only in a small number of cases. CASE-DIAGNOSIS/TREATMENT: Four patients were admitted to our clinic after 15-30 days of life with vomiting associated with poor sucking, failure to thrive, lethargy and hypotonia. Examinations showed thrombocytopenia and microangiopathic hemolytic anemia associated with renal damage. The neonates had high blood homocysteine levels, increased urinary levels of both homocystine and methylmalonic acid, increased propionylcarnitine (C3) levels and an increased C3/acetylcarnitine ratio. Homozygosity for c.271-272dupA (p.Arg91LysfsX14) of the MMACHC gene was detected in three patients, and heterozygosity for c.271-272dupA and c.666C > A(p.Tyr222X) in one patient, which confirmed the diagnosis of Cbl-C disorder. Treatment with parenteral hydroxycobalamin in combination with folic acid and betaine gradually normalized the metabolic test findings and hematological and renal parameters after about 1 week. CONCLUSIONS: Atypical HUS in neonates with Cbl-C disorder may be associated with mild to moderate renal involvement also in early-onset disease, and early adequate therapy can reverse renal damage.

Invasive pneumococcal pneumonia is the major cause of paediatric haemolytic-uraemic syndrome in Taiwan.

AIM: Streptococcus pneumoniae-associated haemolytic uraemic syndrome (SP-HUS) is a major concern of paediatric acute renal failure in Taiwan; it leads to significant morbidity and mortality during the acute phase and to long-term morbidity after an acute episode. METHODS: Twenty children diagnosed with HUS between 1 May 1995, and 31 December 2008 was enrolled. Clinical variables related to laboratory data, organ involved, and outcomes were examined between patients with and without SP-HUS. RESULTS: Thirteen of the 20 (13/20, 65%) patients required dialysis, nine (9/20, 45.0%) developed hepatic dysfunction, disseminated intravascular coagulation (DIC), gastrointestinal bleeding, and hypertension, respectively. They were the second most common extrarenal complication except empyema (11/20, 55%). Two (10%) died and seven (35%) of the survivors developed long-term renal morbidity. Twelve of the 20 patients (60%) were diagnosed with SP-HUS. Younger age, female children, higher white blood cell count, higher alanine transaminase, higher lactate dehydrogenase and high incidence of DIC were significantly common in SP-HUS cases. All SP-HUS cases were complicated with pleural effusion, empyema, or both. Positive Thomsen-Freidenreich antigen (T-Ag) activation was 83% sensitive and 100% specific for SP-HUS, and a positive direct Coombs' test was 58% sensitive and 100% specific. CONCLUSION: Invasive pneumococcal infection is the most common cause of HUS in Taiwan. Positive T-Ag activation and a direct Coombs' test are rapid predictors of SP-HUS in children with invasive pneumonia.

In vitro modeling of the microvascular occlusion and thrombosis that occur in hematologic diseases using microfluidic technology.

In hematologic diseases, such as sickle cell disease (SCD) and hemolytic uremic syndrome (HUS), pathological biophysical interactions among blood cells, endothelial cells, and soluble factors lead to microvascular occlusion and thrombosis. Here, we report an in vitro "endothelialized" microfluidic microvasculature model that recapitulates and integrates this ensemble of pathophysiological processes. Under controlled flow conditions, the model enabled quantitative investigation of how biophysical alterations in hematologic disease collectively lead to microvascular occlusion and thrombosis. Using blood samples from patients with SCD, we investigated how the drug hydroxyurea quantitatively affects microvascular obstruction in SCD, an unresolved issue pivotal to understanding its clinical efficacy in such patients. In addition, we demonstrated that our microsystem can function as an in vitro model of HUS and showed that shear stress influences microvascular thrombosis/obstruction and the efficacy of the drug eptifibatide, which decreases platelet aggregation, in the context of HUS. These experiments establish the versatility and clinical relevance of our microvasculature-on-a-chip model as a biophysical assay of hematologic pathophysiology as well as a drug discovery platform.

Eculizumab in atypical hemolytic uremic syndrome: long-term clinical course and histological findings.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy associated with defective regulation of the alternative complement pathway. The prognosis for patients with aHUS is poor, and plasma exchange represents the first-line therapy. Eculizumab is a humanized monoclonal anti-C5 antibody that prevents the activation of the terminal complement pathway. Here, we report the case of a 9-year-old girl with frequent relapsing aHUS due to heterozygous factor H mutation who was initially treated with plasma exchange three times per week with 150% plasma exchange volume. This treatment frequently caused allergic reactions and school absences. Because any reduction in the frequency of plasma exchange immediately induced relapses of the aHUS, treatment with eculizumab, 600 mg every 2 weeks, was started and plasma exchange completely stopped. On this drug regimen the patient showed no evidence of disease activity during a period of more than 24 months. Renal function improved, proteinuria disappeared, the number of antihypertensive medications could be decreased, and the quality of life increased substantially. The inhibition of the terminal complement pathway by eculizumab was also confirmed by renal biopsy, which showed the absence of thrombotic microangiopathy 2 months after the initiation of eculizumab therapy. This case illustrates the long-term favorable outcome of aHUS with eculizumab treatment.

Characterization of stx2 tubular response in a rat experimental model of hemolytic uremic syndrome.

BACKGROUND/AIMS: In Argentina, hemolytic uremic syndrome (HUS) constitutes the most frequent cause of acute renal failure in children. The aim of our study was to analyze the early tubular response under the effect of Shiga toxin type 2 (Stx2) in a rat experimental model of HUS. METHODS: Adult male Sprague-Dawley rats were injected intraperitoneally with culture supernatant from recombinant Escherichia coli expressing Stx2. Functional, histological, immunohistochemical and Western blot studies were performed at 48 h postinoculation. RESULTS: Renal tubules showed the loss of the epithelial markers E-cadherin and ß-catenin, and an increase in transforming growth factor-ß1 expression. We detected the expression of α-smooth muscle actin in the interstitium and fibrosis in the periglomerular areas. CONCLUSION: Our results indicate that the early tubular response to the effects of Stx2 is related to an immunophenotype change of tubular cells and the presence of mild fibrosis in the interstitium.

Successful isolated liver transplantation in a child with atypical hemolytic uremic syndrome and a mutation in complement factor H.

A male infant was diagnosed with atypical hemolytic uremic syndrome (aHUS) at the age of 5.5 months. Sequencing of the gene (CFH) encoding complement factor H revealed a heterozygous mutation (c.3644G>A, p.Arg1215Gln). Despite maintenance plasmapheresis he developed recurrent episodes of aHUS and vascular access complications while maintaining stable renal function. At the age of 5 years he received an isolated split liver graft following a previously established protocol using pretransplant plasma exchange (PE) and intratransplant plasma infusion. Graft function, renal function and disease remission are preserved 2 years after transplantation. Preemptive liver transplantation prior to the development of end stage renal disease is a valuable option in the management of aHUS associated with CFH mutations.

Thrombotic microangiopathy: new insights.

PURPOSE OF REVIEW: In the following study new aspects and insights into the epidemiology, pathogenesis and typical morphology of kidney involvement in thrombotic microangiopathy (TMA) are discussed. TMA comprises a spectrum of microvascular thrombosis syndromes associated with multiple pathogenetic factors, that is, typical and atypical haemolytic uraemic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), malignant hypertension, drugs or systemic autoimmune diseases or antibody-mediated rejection. RECENT FINDINGS: The present article will put particular emphasis on new pathophysiological insights into the development of TMA in the various settings. In addition, new options in the therapeutic management of TMA in atypical HUS are discussed. The pathogenesis of TMA in atypical HUS primarily involves hereditary or acquired deficiencies and disturbances of the complement system. Eculizumab is a promising new therapeutic option that has been discovered recently. SUMMARY: In HUS/TTP the kidney shows characteristic vascular changes due to endothelial damage, that is, TMA, which should be clinically and morphologically differentiated from other diseases. Recent genetic and molecular studies have shed more light on the pathogenesis of TMA in atypical HUS, that is, disturbances of various aspects of the complement system, and in TTP, that is, von Willebrand factor regulation by ADAMTS13, which are also helpful in the differential diagnosis.

Thrombotic thrombocytopenia purpura (TTP) and other thrombotic microangiopathies.

Thrombotoic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy characterised by systemic platelet aggregation, organ ischaemia, profound thrombocytopenia (with increased marrow megakaryocytes) and fragmentation of erythrocytes. Haemolytic-uraemic syndrome (HUS) is another type of thrombotic microangiopathy accompanied by renal dysfunction. In adults, a thrombotic microangiopathy that clinically more often resembles HUS than TTP may follow: bone marrow or solid organ transplantation and immunosuppression with cyclosporine or tacrolimus; total-body irradiation; mitomycin; gemcitabine; multiple chemotherapeutic agents; or antiangiogenic/antineoplastic substances. This article discusses the thrombotic microangiopathies that have provided the most extensive molecular insights to date into pathophysiology. These are familial and acquired forms of TTP associated with deficient plasma von Willebrand factor (VWF)-cleaving metalloprotease (ADAMTS-13) activity; acquired diarrhoea-associated HUS; the thrombotic microangiopathies associated with cyclosporine/tacrolimus or bevacizumab; and the preeclampsia-HELLP (haemolysis-elevated liver enzymes-low platelets) syndrome.

Pathogenesis of thrombotic microangiopathy: insights from animal models.

Animal models are important experimental tools for investigating the molecular mechanisms, environmental and genetic susceptibilities underlying the development of thrombotic microangiopathies. Large mammal, small animal models, knockout, transgenic and conditional knockout mouse models are available to investigate haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura and vascular endothelial growth factor-associated thrombotic microangiopathy. These models have shown that it is possible to model the human conditions. However, differences in human and rodent physiology mean that caution is required when interpreting the findings. These models offer realistic prospects for identifying and testing novel therapeutic strategies in a range of thrombotic microangiopathies prior to human trials.

Thrombocytopenia and other hot topics.

A frequent issue in the management of cancer patients with thrombosis is thrombocytopenia, whether related to chemotherapy, heparin, or other drugs. The oncologist will have multiple new anticoagulants to choose from in the future, but for now, the effect of these experimental agents on cancer thrombosis is unknown. Despite the effectiveness of anticoagulation in cancer patients, survival benefit remains controversial. Given the ongoing clinical questions and new drugs, anticoagulant therapy in patients with cancer promises to have an exciting future.