Hemolytic Uremic Syndrome

Background

This is a rare condition affecting mostly children under the age of 10. It is characterized by acute renal failure, microangiopathic hemolytic anemia, fever, and thrombocytopenia. Diarrhea and upper respiratory infection are the most common precipitating factors. Most cases of HUS occur after an infection in the digestive system caused by the Escherichia coli bacterium.
The first stages of HUS frequently present with gastrointestinal symptoms such as abdominal pain, vomiting, and bloody diarrhea. This stage lasts from 1 to 15 days and recovery from this acute colitic phase is the usual outcome. However, more severe problems in the bowel and colon may develop in some cases.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/Immunohistochemistry/Electron Microscopy

Differential Diagnosis

Prognosis and Treatment

Commonly Used Terms

EPIDEMIOLOGY CHARACTERIZATION

SYNONYMS HUS

INCIDENCE Most common cause of acute renal failure in children

Nationwide study of haemolytic uraemic syndrome: clinical, microbiological, and epidemiological features.

Elliott EJ, Robins-Browne RM, O'Loughlin EV, Bennett-Wood V, Bourke J, Henning P, Hogg GG, Knight J, Powell H, Redmond D; Contributors to the Australian Paediatric Surveillance Unit.

Department of Paediatrics and Child Health, University of Sydney and The Children's Hospital at Westmead, Sydney, Australia
Arch Dis Child 2001 Aug;85(2):125-31 Abstract quote
AIMS: To establish the incidence and aetiology of haemolytic uraemic syndrome (HUS) in Australia and compare clinical and microbial characteristics of sporadic and outbreak cases.

METHODS: National active surveillance through the Australian Paediatric Surveillance Unit with monthly case notification from paediatricians, July 1994 to June 1998. Children under 15 years presenting with microangiopathic haemolytic anaemia, thrombocytopenia, and acute renal impairment were identified.

RESULTS: Ninety eight cases were identified (incidence 0.64 per 10(5) children <15 years/annum and 1.35 per 10(5) children <5 years/annum). Eighty four were associated with diarrhoea (64 sporadic, 20 constituting an outbreak) and 14 were atypical. Shiga toxin producing Escherichia coli (STEC) O111:H- was the most common isolate in sporadic HUS and caused the outbreak. However O111:H- isolates from outbreak and sporadic cases differed in phage type and subtyping by DNA electrophoresis. STEC isolates from sporadic cases included O26:H-, O113:H21, O130:H11, OR:H9, O157:H-, ONT:H7, and ONT:H-. STEC O157:H7 was not isolated from any case. Only O111:H- isolates produced both Shiga toxins 1 and 2 and possessed genes encoding E coli attaching and effacing gene (intimin) and enterohemolysin. Outbreak cases had worse gastrointestinal and renal disease at presentation and more extrarenal complications.

CONCLUSIONS: Linking national surveillance with a specialised laboratory service allowed estimation of HUS incidence and provided information on its aetiology. In contrast to North America, Japan, and the British Isles, STEC O157:H7 is rare in Australia; however, non-O157:H7 STEC cause severe disease including outbreaks. Disease severity in outbreak cases may relate to yet unidentified virulence factors of the O111:H- strain isolated.

Growth and survival of Escherichia coli O157: H7 in meat, poultry and vegetables mixed with different concentrations of mayonnaise.

Arias ML, Monge-Rojas R, Antillon F, Chaves C.

Facultad de Microbiologia, Universidad de Costa Rica, 2060 San Jose, Costa Rica.
Rev Biol Trop 2001 Sep-Dec;49(3-4):1207-12 Abstract quote
In the last 20 years Escherichia coli O157: H7 has emerged as a new pathogen, causing worldwide disease, death and economic loss. Different studies have revealed important survival characteristics of this pathogen, although there are divergent criteria about its ability to survive in various mayonnaise formulations.

We studied the effect of different mayonnaise concentrations (0%, 18%, 37% and 56%) (weight/weight) over the survival of the bacterium in common foods from a neotropical environment (Costa Rica). High [10(7)-10(8) Colony Forming Units (CFU)/ml] and low E. coli populations (10(4)-10(6) CFU/ml) were inoculated, (three replicates) in meat, chopped cabbage and poultry, and mixed with commercial mayonnaise to obtain the concentrations specified. They were incubated at 12 degrees C for 24, 48 and 72 hr. The E. coli O157: H7 enumeration was done according to a standard methodology. Populations of E. coli O157: H7 showed an increasing trend during the first incubation period (48 hr), in all the preparations, regardless of the fat concentration used.

Our data indicate that E. coli O157: H7 is capable of surviving and growing in meat, cabbage and poultry mixed with mayonnaise, independently of its concentration.

Population-based trends in pediatric hemolytic uremic syndrome in California, 1994-1999: substantial underreporting and public health implications.

Cummings KC, Mohle-Boetani JC, Werner SB, Vugia DJ.

Disease Investigations and Surveillance Branch, Division of Communicable Disease Control, California Department of Health Services, Berkeley 94704, USA.
Am J Epidemiol 2002 May 15;155(10):941-8 Abstract quote
This paper describes the epidemiology of childhood hemolytic uremic syndrome (HUS) in California, for which hospitalization data were used, and the proportion of cases reported to public health authorities. HUS discharge data for children < or =17 years of age were extracted from the population-based California Patient Discharge Data Set for 1994-1999 and were linked electronically with HUS reports to public health authorities. Incidence rates per 100,000 children were calculated.

The authors identified 585 HUS hospitalizations; 369 were incident cases. The average HUS incidence rate was 0.67 (95% confidence interval: 0.61, 0.74); rates rose modestly from 1994 (0.59, 95% confidence interval: 0.44, 0.78) to 1997 (0.80, 95% confidence interval: 0.63, 10.0) and decreased modestly thereafter (0.59, 95% confidence interval: 0.45, 0.77). Rates were highest for northern California children < or =5 years of age (1.85, 95% confidence interval: 1.55, 2.19). The hospital case-fatality rate was 2.7% (95% confidence interval: 1.1, 4.4); the median charge was $39,500 per child. Only 43.9% of HUS cases in the California Patient Discharge Data Set were reported to public health authorities.

Despite heightened efforts to control Shiga toxin-producing Escherichia coli exposures (the predominant cause of childhood HUS in the United States), HUS incidence rates remained relatively stable in California. Reporting HUS cases to public health authorities is important for disease control.

DISEASE ASSOCIATIONS CHARACTERIZATION

ANTIBIOTICS

Ciprofloxacin-associated hemolytic-uremic syndrome.

Allan DS, Thompson CM, Barr RM, Clark WF, Chin-Yee IH.

David S Allan MSc MD, Hematology Fellow, University of Western Ontario, London, Ontario, Canada.
Ann Pharmacother 2002 Jun;36(6):1000-2 Abstract quote
OBJECTIVE: To report the first case of ciprofloxacin-associated hemolytic-uremic syndrome (HUS).

CASE SUMMARY: A 53-year-old white man was treated with chemotherapy for acute lymphoblastic leukemia. Four weeks after initiation of treatment, he recovered his blood cell counts, but developed fever and was prescribed oral ciprofloxacin 500 mg twice daily. After 4 doses, he developed the typical features of HUS manifested by microangiopathic hemolytic anemia, oliguric renal failure, and thrombocytopenia. The medication was withdrawn, and he received 5 sessions of plasma exchange. He recovered completely and has normal renal function.

DISCUSSION: Secondary HUS or its related syndrome, thrombotic thrombocytopenic purpura (TTP), is uncommon, but has been reported in association with cancer, chemotherapy, and a variety of medications. Our case represents a possible adverse drug reaction to ciprofloxacin according to the Naranjo probability scale. It is the first reported case of HUS associated with ciprofloxacin.

CONCLUSIONS: Ciprofloxacin use was followed by HUS in our patient and was possibly causally related. Early detection, discontinuation of the offending medication, and treatment of HUS/TTP is critical.

CHEMOTHERAPY

Hemolytic uremic syndrome after chemotherapy with gemcitabine and taxotere: a case report.

Citarrella P, Gebbia V, Teresi M, Miceli S, Sciortino G, Vaglica M, Pizzardi N, Palmeri S.

Division of Oncohematology, University of Palermo, Italy.
Anticancer Res 2002 Mar-Apr;22(2B):1183-5 Abstract quote
A case of hemolytic uremic syndrome is reported in a female patient affected by metastatic breast carcinoma receiving chemotherapy with gemcitabine and docetaxel.

Up to now this is the first case that has been reported in the medical literature in patients treated with docetaxel (taxotere)and gemcitabine. The patient developed hemolytic uremic syndrome after the third cycle of chemotherapy. She was treated with diuretics, steroids, antibiotics, antifungal drugs, erythropoietin and fluid replacement. The patient underwest dialysis, and survived the hemolytic uremic syndrome.

It was not possible to ascertain if the hemolytic uremic syndrome was related to the chemotheraputic treatment or the cancer itself.

HIV

Chronic diarrhea, hemorrhagic colitis, and hemolytic-uremic syndrome associated with HEp-2 adherent Escherichia coli in adults infected with human immunodeficiency virus in Bangui, Central African Republic.

Mossoro C, Glaziou P, Yassibanda S, Lan NT, Bekondi C, Minssart P, Bernier C, Le Bouguenec C, Germani Y.

Unite des Maladies Infectieuses Opportunistes, Institut Pasteur de Bangui, Central African Republic.
J Clin Microbiol 2002 Aug;40(8):3086-8 Abstract quote
In human immunodeficiency virus (HIV)-infected adults from the Central African Republic, the occurrence of chronic diarrhea due to HEp-2 adherent Escherichia coli (EAEC) harboring virulence markers (eaeA, BFP, EAF, astA determinant of EAST/1, positive FAS test, enteropathogenic E. coli O serogroup) was shown to be associated with AIDS.

We also show that EAEC that produce verotoxin (Stx2) but do not harbor the genetic markers for classical enterohemorrhagic E. coli are involved in hemorrhagic colitis and hemolytic-uremic syndrome in patients with HIV.

PNEUMOCOCCAL DISEASE

Prognosis of Streptococcus pneumoniae-induced hemolytic uremic syndrome.

Nathanson S, Deschenes G.

Service de Nephrologie Pediatrique, Hopital Armand-Trousseau, 26 Avenue Arnold-Netter, 75571 Paris, France.
Pediatr Nephrol 2001 Apr;16(4):362-5 Abstract quote
Streptococcus pneumoniae-induced hemolytic uremic syndrome (HUS) is known to be a severe acute disease leading to death in one-third of cases, but data regarding the long-term follow-up are lacking.

A new series of 11 patients with Streptococcus pneumoniae-induced HUS associated with meningitis and pneumonia constituted a multi-center review. Among 9 patients with a severe acute infectious disease, 3 died from meningitis and 1 from neurological sequelae after a partial recovery of renal function.

The mean duration of dialysis was 32 days in patients with acute renal failure who survived the acute infectious period. Cortical necrosis was documented in five of six kidney specimens. Among the 7 surviving patients, 5 developed end-stage renal failure 4-17 years later.

Invasive pneumococcal disease and hemolytic uremic syndrome.

Brandt J, Wong C, Mihm S, Roberts J, Smith J, Brewer E, Thiagarajan R, Warady B.

Department of Pediatrics, Children's Hospital of New Mexico, Albuquerque, New Mexico 87131-5311, USA.
Pediatrics 2002 Aug;110(2 Pt 1):371-6 Abstract quote
OBJECTIVE: Severe pneumococcal infections have been associated with hemolytic uremic syndrome (HUS), usually with a poor clinical outcome when compared with Escherichia coli O157 gastroenteritis-associated (D+) HUS. We examined our experience with 12 cases of Streptococcus pneumoniae-associated HUS (SP-HUS) and compare it with a cohort of diarrhea-associated HUS (D+ HUS).

METHODS: A retrospective case survey compared 2 unrelated groups of HUS patients. Demographic factors, clinical indices of disease severity, and outcome were used to compare the 2 groups of HUS patients.

RESULTS: Twelve children with SP-HUS were studied. Pneumococcal pneumonia with empyema was the most common precipitating illness (67%), pneumococcal meningitis was present in 17% of children, pneumonia with bacteremia in 8%, and both pneumonia and meningitis in 8%. SP-HUS patients were younger than D+ HUS patients (22.1 vs 49 months) and had more severe renal and hematologic disease than D+ HUS patients. Compared with D+ HUS patients, SP-HUS patients were more likely to require dialysis (75% vs 59%) and had a longer duration of hospitalization (33.2 vs 16.1 days) and duration of thrombocytopenia (11.6 vs 6.8 days). SP-HUS patients were also more likely to require platelet transfusions (83% vs 47%) and needed more platelet (4.7 vs 0.5) and packed red blood cell transfusions (7.8 vs 2.0). The 2 groups did not differ significantly in the incidence of extrarenal HUS complications. There were no deaths in either group. Seven patients have been seen for long-term follow-up; 2 developed end-stage renal disease, and 5 have normal renal function.

CONCLUSIONS: HUS is a rare but severe complication of invasive pneumococcal infection. Although disseminated intravascular coagulation can also occur in these children, the treatment and follow-up may be different in the 2 conditions. Children with pneumococcal disease and severe hematologic or renal abnormalities should be investigated for evidence of HUS.

PATHOGENESIS CHARACTERIZATION

GENERAL
E. coli, Shigella, Salmonella, Yersinia, and Campylobacter species

ANIMAL MODEL

Gnotobiotic piglets develop thrombotic microangiopathy after oral infection with enterohemorrhagic Escherichia coli.

Gunzer F, Hennig-Pauka I, Waldmann KH, Sandhoff R, Grone HJ, Kreipe HH, Matussek A, Mengel M.

Institute of Medical Microbiology, Hannover Medical School, Germany.
Am J Clin Pathol 2002 Sep;118(3):364-75 Abstract quote
Oral infection with enterohemorrhagic Escherichia coli (EHEC) may cause severe enteritis, followed in up to 10% of cases by an extraintestinal complication, the hemolytic uremic syndrome (HUS).

HUS is characterized by a triad of symptoms: anemia, thrombocytopenia, and acute renalfailure due to thrombotic microangiopathy. EHEC produces several virulence factors, among which a family of phage-encoded cytotoxins, called Shiga toxin 1 and Shiga toxin 2, seems to be most important. However, since an appropriate animal model is not available, pathogenicity of these emerging enteric pathogens is still poorly understood. Germ-free gnotobiotic piglets infected orally with an O1577:H7 or an O26:H11 EHEC wild-type isolate, both producing Shiga toxin 2, developed intestinal and extraintestinal manifestations of EHEC disease, including thrombotic microangiopathy in the kidneys, the morphologic hallmark of HUS in humans.

Thus, gnotobiotic piglets are suitable to further study the pathophysiology of EHEC-induced HUS. It can be expected that data obtainedfrom this animal model will improve our current standard of knowledge about this emerging infectious disease.

BASIC FIBROBLASTIC GROWTH FACTOR

Basic fibroblast growth factor among children with diarrhea-associated hemolytic uremic syndrome.

Ray P, Acheson D, Chitrakar R, Cnaan A, Gibbs K, Hirschman GH, Christen E, Trachtman H; The Investigators of the Hemolytic Uremic Syndrome-Synsorb PK Multicenter Clinical Trial.

Department of Pediatrics, Children's National Medical Center, Washington, DC, USA

J Am Soc Nephrol 2002 Mar;13(3):699-707 Abstract quote
Diarrhea-associated hemolytic uremic syndrome (D+HUS) is characterized by endothelial injury and activation of inflammatory cytokines. Basic fibroblast growth factor (bFGF) is an angiogenic peptide released in response to vascular damage.

The plasma concentrations and urinary excretion of bFGF during the course of D+HUS were determined, in comparison with the levels of various inflammatory cytokines, and changes were correlated with clinical and laboratory features of the disease. Serial plasma and urine samples were collected from 31 children with D+HUS, during the acute (days 1 to 7 of hospitalization) and recovery (through day 60 after discharge from the hospital) phases of the disease. The patients were enrolled in the multicenter trial of SYNSORB Pk (SYNSORB Biotech, Calgary, Alberta, Canada) treatment for D+HUS. bFGF, interleukin-1alpha (IL-1alpha), IL-8, and tumor necrosis factor-alpha levels were determined with enzyme-linked immunosorbent assays. bFGF was detected in urine and plasma samples more frequently than were IL-1alpha, IL-8, and tumor necrosis factor-alpha. There was an acute increase in urinary bFGF excretion, which returned to normal during convalescence.

Urinary excretion of bFGF during the acute phase was higher among patients who required dialysis, compared with those who did not (48.9 +/- 15.0 and 28.9 +/- 9.0 pg/ml, respectively; P < 0.05). Plasma bFGF concentrations were persistently elevated throughout the period of hospitalization and the follow-up period among patients with D+HUS. Urinary excretion and plasma levels of bFGF were comparable for the SYNSORB Pk-treated (n = 19) and placebo-treated (n = 12) groups.

Measurements of urinary and plasma concentrations of bFGF among patients with D+HUS may be useful indices for assessment of the severity of acute renal disease and the timing and adequacy of the systemic angiogenic process during early convalescence.

COMPLEMENT FACTOR H

Complement factor H and hemolytic uremic syndrome.

Zipfel PF, Skerka C, Caprioli J, Manuelian T, Neumann HH, Noris M, Remuzzi G.

Department of Infection Biology, Hans Knoell Institute for Natural Products Research, Beutenbergstr. I1a, 07745 Jena, Germany.
Int Immunopharmacol 2001 Mar;1(3):461-8 Abstract quote
Factor H is a 150 kDa single chain plasma glycoprotein that plays a pivotal role in the regulation of the alternative pathway of complement. Primary sequence analysis reveals a structural organization of this plasma protein, in 20 homologous units, called Short Consensus Repeats (SCRs), each about 60 amino acids long. Biochemical and genetic studies show an association between factor H deficiency and human diseases, including Systemic Lupus Erythematosus, susceptibility to pyogenic infection and a form of membranoproliferative glomerulonephropathy. More recently, factor H deficiency has also been associated with susceptibility to Hemolytic Uremic Syndrome (HUS), a disease consisting of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure, caused by platelet thrombi which mainly, but not exclusively, form in the microcirculation of the kidney.

In this review, we summarize recent genetic and biochemical data, which indicate a critical role for factor H in the pathogenesis of HUS and suggest an important role of the most C-terminal domain, i.e. SCR 20, in the disease. In addition, we discuss the physiological consequences of these findings, as novel functional data show a particular essential role of SCR 20 of factor H as the central discriminatory and regulatory site of this multidomain, multifunctional plasma protein.

E. COLI 0157:H7

Regulation of virulence factors of enterohemorrhagic Escherichia coli O157:H7 by self-produced extracellular factors.

Kanamaru K, Kanamaru K, Tatsuno I, Tobe T, Sasakawa C.

Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan.
Biosci Biotechnol Biochem 2000 Nov;64(11):2508-11 Abstract quote
Enterohemorrhagic Escherichia coli (EHEC) O157:H7 causes serious diarrhea and hemolytic uremic syndrome in humans. The expressions of EspD and intimin by O157:H7 have now been shown to be down-regulated by medium conditioned by O157:H7 grown at stationary phase.

Preparation of conditioned medium showing the effect on the amount of EspD was not dependent on temperature or growth medium, but was dependent on growth phase. Inhibition of EspD and intimin expression was also induced by medium conditioned by E. coli K-12 strains and homoserine lactone, a signal molecule of the quorum-sensing system in gram-negative bacteria.

These results suggest the possibility that the quorum-sensing system mediated by self-produced extracellular factors plays an important role in control of colonization of EHEC O157:H7.

Complete genome sequence of enterohemorrhagic Escherichia coli O157:H7 and genomic comparison with a laboratory strain K-12.

Hayashi T, Makino K, Ohnishi M, Kurokawa K, Ishii K, Yokoyama K, Han CG, Ohtsubo E, Nakayama K, Murata T, Tanaka M, Tobe T, Iida T, Takami H, Honda T, Sasakawa C, Ogasawara N, Yasunaga T, Kuhara S, Shiba T, Hattori M, Shinagawa H.

Department of Microbiology, Miyazaki Medical College, Kiyotake, Japan.
DNA Res 2001 Feb 28;8(1):11-22 Abstract quote
Escherichia coli O157:H7 is a major food-borne infectious pathogen that causes diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome. Here we report the complete chromosome sequence of an O157:H7 strain isolated from the Sakai outbreak, and the results of genomic comparison with a benign laboratory strain, K-12 MG1655. The chromosome is 5.5 Mb in size, 859 Kb larger than that of K-12.

We identified a 4.1-Mb sequence highly conserved between the two strains, which may represent the fundamental backbone of the E. coli chromosome. The remaining 1.4-Mb sequence comprises of O157:H7-specific sequences, most of which are horizontally transferred foreign DNAs. The predominant roles of bacteriophages in the emergence of O157:H7 is evident by the presence of 24 prophages and prophage-like elements that occupy more than half of the O157:H7-specific sequences. The O157:H7 chromosome encodes 1632 proteins and 20 tRNAs that are not present in K-12. Among these, at least 131 proteins are assumed to have virulence-related functions. Genome-wide codon usage analysis suggested that the O157:H7-specific tRNAs are involved in the efficient expression of the strain-specific genes.

A complete set of the genes specific to O157:H7 presented here sheds new insight into the pathogenicity and the physiology of O157:H7, and will open a way to fully understand the molecular mechanisms underlying the O157:H7 infection.

ENDOTHELIUM

The role of the endothelium in hemolytic uremic syndrome.

Zoja C, Morigi M, Remuzzi G.

Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
J Nephrol 2001 Nov-Dec;14 Suppl 4:S58-62 Abstract quote
Hemolytic uremic syndrome (HUS), which is the most common cause of acute renal failure in children, is caused by Shiga toxin-producing Escherichia coli infection. This infection leads to renal and other organ microvascular thrombosis. Endothelial injury has been recognized as the trigger event in the development of microangiopathic process.

Evidence suggests that leukocyte as well as platelet activation participate in endothelial damage. Intrinsic abnormalities of the complement system may also play a role in HUS.

TOXINS Shiga and Shigalike toxins, produced by some strains of Shigella dysenteriae and E coli 0157:H7
70% of cases of HUS in children

Pathogenesis of Shiga toxin-induced hemolytic uremic syndrome.

Ray PE, Liu XH.

Children's Research Institute, Research Center for Molecular Physiology, Washington, DC, USA.
Pediatr Nephrol 2001 Oct;16(10):823-39 Abstract quote
The term hemolytic uremic syndrome (HUS) was first introduced to describe a heterogeneous group of diseases characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Substantial progress has been made in our understanding of the etiology and pathogenesis of HUS.

This article reviews some of the classic and new concepts related to the pathogenesis of Shiga toxin (Stx)-HUS and discusses their clinical relevance for the diagnosis and treatment of this syndrome. Infection with Stx-producing bacteria can induce HUS after a prodromal illness with or without diarrhea. Stx-induced renal endothelial injury is the primary pathogenic event. However, Stx also damages mesangial cells, as well as glomerular and renal tubular epithelial cells. Young children are at greatest risk for Stx-HUS because they express high levels of Stx receptors in renal glomeruli. Older children and adults express lower levels of glomerular Stx receptors and may develop Stx-HUS whenever the combined effects of lipopolysaccharide and cytokines upregulate the expression of Stx receptors and sensitize glomerular endothelial cells to Stx-induced injury, activate the coagulation-fibrinolytic system, and induce endothelial injury. Chemokine receptors and cytokines released by inflammatory cells (i.e., monocyte chemoattractant protein-1, interleukin-6, interleukin-8,) or injured endothelial cells (i.e., basic fibrobast growth factor) may play roles in this process.

Measurement of the activity of a von Willebrand factor protease in plasma may help distinguish patients with thrombotic thrombocytopenic purpura from those with Stx-HUS.

von WILLEBRAND FACTOR-CLEAVING PROTEASE

Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases.

Veyradier A, Obert B, Houllier A, Meyer D, Girma JP.

INSERM Unite 143, Le Kremlin Bicetre, France.
Blood 2001 Sep 15;98(6):1765-72 Abstract quote
Retrospective studies of patients with thrombotic microangiopathies (TMAs) have shown that a deficient activity of von Willebrand factor (vWF)-cleaving protease is involved in thrombotic thrombocytopenic purpura (TTP) but not in the hemolytic-uremic syndrome (HUS).

To further analyze the relevance of this enzymatic activity in TMA diagnosis, a 20-month multicenter study of vWF-cleaving protease activity was conducted in adult patients prospectively enrolled in the acute phase of TMA. Patients with sporadic (n = 85), intermittent (n = 21), or familial recurrent (n = 5) forms of TMA (66 manifesting as TTP and 45 as HUS) were included. TMA was either idiopathic (n = 42) or secondary to an identified clinical context (n = 69). vWF-cleaving protease activity was normal in 46 cases (7 TTP and 39 HUS) and decreased in 65 cases (59 TTP and 6 HUS). A protease inhibitor was detected in 31 cases and was observed only in patients manifesting TTP with a total absence of protease activity.

Among the 111 patients, mean vWF antigen levels were increased and the multimeric distribution of vWF was very heterogeneous, showing either a defect of the high-molecular-weight forms (n = 40), a normal pattern (n = 21), or the presence of unusually large multimers (n = 50).

Statistical analysis showed that vWF-protease deficiency was associated with the severity of thrombocytopenia (P <.01). This study emphasizes that vWF-cleaving protease deficiency specifically concerns a subgroup of TMA corresponding to the TTP entity.

Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease.

Furlan M, Lammle B.

Central Hematology Laboratory, University Hospital, Inselspital, Bern, Switzerland.

Best Pract Res Clin Haematol 2001 Jun;14(2):437-54 Abstract quote
Thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS) are today often regarded as variants of one syndrome denoted as TTP/HUS, characterized by thrombocytopenia caused by intravascular platelet clumping, microangiopathic haemolytic anaemia, fever, renal abnormalities and neurological disturbances. Unusually large von Willebrand factor multimers have been observed in plasma from patients with chronic relapsing forms of TTP. Their appearance in patients with classic TTP is caused by deficiency of a specific von Willebrand factor-cleaving protease. A constitutional deficiency of this protease has consistently been found in familial cases of TTP, whereas in acquired TTP the protease deficiency is caused by the presence of an inhibiting autoantibody. A normal activity of von Willebrand factor-cleaving protease has been established in patients with HUS.

In this chapter, we report 23 cases with severe constitutional protease deficiency: about one half of these patients had their first acute episode as children, whereas the other half had their first TTP event at an adult age, several of them during their first pregnancy. Two of these 23 individuals with congenital protease deficiency, both older than 35 years, have never had an acute TTP event. These results indicate that a deficiency of von Willebrand factor-cleaving protease alone is not sufficient to cause acute TTP. Patients with long-lasting dormant protease deficiency have been found to experience multiple relapses of TTP after having had their first acute episode. In one protease-deficient, plasma-dependent patient with chronic relapsing TTP, we estimated that 5% of normal protease activity is sufficient to remove the most adhesive von Willebrand factor multimers and prevent the formation of platelet microthrombi. The deficiency of von Willebrand factor-cleaving protease is a very strong risk factor for TTP, but the development of an acute bout requires a trigger, possibly causing the activation or apoptosis of endothelial cells in the microcirculation. It is unclear whether anti-endothelial cell antibodies, cytokines or other agents are involved in triggering thrombotic microangiopathy. The release of platelet calpain (and/or other proteases), leading to a degradation of von Willebrand factor and to platelet aggregation, has been reported in patients during their acute TTP episode. It is unknown whether calpain directly triggers an acute event or whether it merely reflects its release during the aggregation of platelets by the unusually large von Willebrand factor multimers.

With regard to the heterogeneous aetiology of thrombotic microangiopathies, requiring distinct therapeutic measures, a new classification of thrombotic microangiopathy should replace the current, frequently inappropriate clinical discrimination between TTP and haemolytic uraemic syndrome.

LABORATORY/RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

Changes of renal flow volume in the hemolytic-uremic syndrome--color Doppler sonographic investigations.

Scholbach TM.

KinderKlinik St. Georg, Leipzig, Germany.
Pediatr Nephrol 2001 Aug;16(8):644-7 Abstract quote
Varying degrees of vascular occlusion can be found in the hemolytic-uremic syndrome (HUS). This is the rationale for Doppler sonographic investigations of renal blood flow in children with HUS.

In 1989 a first report suggested a close relationship between normalization of the resistive index (RI) of renal blood flow with the restitution of urine flow in affected children. Later reports did not confirm these initial findings. The aim of this paper is to describe renal volume perfusion quantitatively in children with HUS. The renal arteries in 35 patients with HUS (1 month to 15 years) were investigated at the onset of HUS by color Doppler ultrasonography. Flow volume measurements were carried out in the 1st week and in the 2nd to 4th week after onset of the disease. These data were compared with measurements from a healthy pediatric population of 69 children. Statistically significant changes in renal perfusion occur in the flow volume of the kidneys. The flow volume dropped to 32% (34%) in the 1st week of the disease compared with the normal population and recovered in 2-4 weeks to 117% (65%) of the normal flow volume (left kidney in parentheses).

The new technique of volumetric perfusion measurement overcomes some drawbacks of the traditional RI, which may have led to some confusion in the past.

LABORATORY MARKERS

LEUKOCYTOSIS

LEUKOCYTOSIS

Leukocytosis in children with Escherichia coli O157:H7 enteritis developing the hemolytic-uremic syndrome.

Buteau C, Proulx F, Chaibou M, Raymond D, Clermont MJ, Mariscalco MM, Lebel MH, Seidman E.

Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Quebec, Canada.

Pediatr Infect Dis J 2000 Jul;19(7):642-7 Abstract quote
BACKGROUND: Fewer than 10% of children with Escherichia coli O157:H7 enteritis develop hemolytic-uremic syndrome (HUS).

OBJECTIVE: To determine whether circulating leukocytes are independent risk markers of developing HUS during E. coli O157:H7 enteritis.

METHODS: We reviewed the charts of all children with culture-proved E. coli O157:H7 infections seen at Sainte-Justine Hospital between 1987 and 1997. Epidemiologic data, laboratory indices and circulating leukocytes counts were noted. HUS diagnosis was validated with independent HUS patient lists from the pediatric nephrology services of tertiary care hospitals in the Montreal metropolitan area. The date of onset of enteritis was determined by two independent observers. Leukocyte counts were compared among the following independent groups: (1) uncomplicated O157:H7 enteritis (Group 1); (2) O157:H7 enteritis with the subsequent development of HUS (Group 2); (3) HUS already present at the time of medical consultation (Group 3).

RESULTS: There were 369 children with E. coli O157:H7 infection. A complete blood count was not performed in 114 (31%) patients. Observers disagreed on the date of onset of gastroenteritis in 34 (9%) children only (kappa 0.92). The study population thus included 221 patients: Group 1, n = 161; Group 2, n = 27; and Group 3, n = 33. Patients developing HUS (Group 2) presented greater total leukocyte (P < 0.008), polymorphonuclear (P < 0.008) and monocyte (P < 0.07) counts than those with an uncomplicated course (Group 1). Logistic regression analysis showed that young age [odds ratio (OR), 0.98; 95% confidence interval (CI), 0.96 to 0.99], duration of enteric prodrome < or =3 days (OR 4.8, 95% CI 1.13 to 20.7) and initial leukocytosis (OR 1.22, 95% CI, 1.11 to 1.35) were independent predictors of HUS.

CONCLUSIONS: Based on the variables identified above, further studies are needed to determine whether the inflammatory response of the host represents only a marker of the severity of gastrointestinal infection or whether, alternatively, it is a pathophysiologic factor that leads to HUS.

PHAGE TYPING

Phage typing and DNA-based comparison of strains of enterohemorrhagic Escherichia coli O157 from apparently sporadic infections in Osaka City, Japan, 1996.

Nishikawa Y, Hase A, Ogasawara J, Cheasty T, Willshaw GA, Smith HR, Tatsumi Y, Yasukawa A.

Department of Epidemiology, Osaka City Institute of Public Health and Environmental Sciences, Osaka 543-0026, Japan
Jpn J Infect Dis 2001 Aug;54(4):140-3 Abstract quote
A marked increase in sporadic cases of enteritis due to enterohemorrhagic Escherichia coli serogroup O157 occurred in Osaka City, Japan, during 1996.

To elucidate why the number of cases had increased, the isolates were classified using phage typing, random amplified polymorphic DNA analysis, and pulsed-field gel electrophoresis (PFGE). Fifty-seven percent of the isolates (105/184) belonged to the same phage type (PT-32) and gave the same PFGE pattern; the clone had been isolated during a 3-week period, with a peak on July 15.

It was concluded that the majority of the cases identified in July 1996 formed an outbreak, although epidemiological links to a possible common source were not established. The possibility that this outbreak was part of a huge regional outbreak including children at primary schools in Sakai City was discussed.

TISSUE FACTOR

Elevated tissue factor circulating levels in children with hemolytic uremic syndrome caused by verotoxin-producing E. coli.

Kamitsuji H, Nonami K, Murakami T, Ishikawa N, Nakayama A, Umeki Y.

Department of Pediatrics, Nara Prefectural Nara Hospital, Hiramatsu, Japan.
Clin Nephrol 2000 May;53(5):319-24 Abstract quote
BACKGROUND: Microvascular thrombosis in the kidney plays an important role in the pathogenesis of hemolytic uremic syndrome (HUS). Tissue factor (TF), present on the vascular surface of endothelial cells, binds factor VIIa. The complex initiates the coagulating cascade by activating factors X and IX.

PATIENTS AND METHODS: In cases of HUS associated with verotoxin-producing E. coli (VTEC) infection, VTEC gastroenteritis without HUS and normal controls, we measured plasma concentrations of TF and tissue factor pathway inhibitor (TFPI) to evaluate their clinical significance. In children with non-HUS chronic renal failure (CRF), the TF levels were also measured as another control group.

RESULTS: In the acute phase of HUS, plasma levels of TF and TFPI were significantly elevated, then returned to normal range in the recovery phase. The TF levels were closely correlated with the thrombin antithrombin-III complex, a marker of thrombin activity in circulating blood, and with creatinine clearance (Ccr). Furthermore, a positive correlation was noted between plasma TF levels and plasma soluble thrombomodulin (sTM) levels, which is a marker of endothelial cell injury. The influence of decreased excretion from damaged kidneys should be considered since a definite lot correlation was observed between plasma TF levels and Ccr in children with non-HUS CRF.

CONCLUSION: From these findings, we concluded that elevated TF circulating levels may also play an important role in blood-clotting activation observed in VTEC-HUS patients, and may also be a useful marker for renal damage.

von WILLEBRAND FACTOR-CLEAVING PROTEASE

Assays of von Willebrand factor- cleaving protease: a test for diagnosis of familial and acquired thrombotic thrombocytopenic purpura.

Furlan M, Lammle B.

Central Hematology Laboratory, University Hospital, Inselspital, Bern, Switzerland.
Semin Thromb Hemost 2002 Apr;28(2):167-72 Abstract quote
Endothelial cells secrete von Willebrand factor (vWF) multimers that are larger than those found in the circulating plasma. These very large multimeric forms of vWF, capable of spontaneously binding to and agglutinating the blood platelets under conditions of high fluid shear rate, are degraded by a specific metalloprotease cleaving the peptide bond 842Tyr-843Met of the vWF subunit.

The vWF-cleaving protease was found to be deficient in patients with familial thrombotic thrombocytopenic purpura (TTP). The acute events in these patients can be successfully treated and prophylactically prevented by repletion of the missing protease using fresh frozen plasma (FFP). In another, apparently more common, form of TTP, the protease deficiency is due to inhibiting circulating antibodies directed against the vWF-cleaving protease. Therapy of these patients should include immunosuppressive treatment in addition to plasma exchange and replacement with FFP.

Normal activity of vWF-cleaving protease was established in patients with a clinically similar disorder: hemolytic-uremic syndrome (HUS). The level of vWF-cleaving protease activity is thus a laboratory parameter that provides important information for the differential diagnosis and treatment of patients with TTP/HUS. Several assays of vWF-cleaving protease have been described and are summarized here.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

The United States National Prospective Hemolytic Uremic Syndrome Study: microbiologic, serologic, clinical, and epidemiologic findings.

Banatvala N, Griffin PM, Greene KD, Barrett TJ, Bibb WF, Green JH, Wells JG; Hemolytic Uremic Syndrome Study Collaborators.

Foodborne and Diarrheal Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
J Infect Dis 2001 Apr 1;183(7):1063-70 Abstract quote
The frequency of Shiga toxin-producing Escherichia coli (STEC) serotypes associated with postdiarrheal hemolytic uremic syndrome (HUS) cases among children and adults in the United States and the proportion with IgM or IgG lipopolysaccharide antibodies to E. coli O157 were determined by use of a nationwide sample from January 1987 through December 1991.

Among 83 patients, STEC were isolated from 30 (43%) of 70 whose stool cultures yielded bacterial growth (25 E. coli O157 isolates and 5 non-O157 STEC isolates). Fifty-three (80%) of 66 patients with serum samples had positive O157 lipopolysaccharide antibody titers. Of the 83 patients, 60 (72%) had evidence of STEC infection, including 6 of 8 adults whose illnesses also met criteria for thrombotic thrombocytopenic purpura.

Data from a subset of patients suggest that E. coli O157 was the cause of > or = 80% of the STEC infections. All 3 women who were postpartum had evidence of E. coli O157 infection. STEC infection should be considered the likely cause for all persons with postdiarrheal HUS.

Hemolytic-uremic syndrome.

Corrigan JJ Jr, Boineau FG.
Pediatr Rev 2001 Nov;22(11):365-9 Abstract quote
The hemolytic-uremic syndrome (HUS) has been recognized for more than 45 years and consists of the combination of hemolytic anemia, thrombocytopenia, and acute renal failure. HUS occurs predominantly in children younger than 4 years of age.

It is the most frequent cause of acute renal failure in children. The most common form of the syndrome (D+ HUS) occurs in healthy young children (>6 mo to <5 y of age) and is preceded by watery diarrhea that can evolve to hemorrhagic colitis. The diarrhea precedes the hemolysis and thrombocytopenia by 5 to 7 days; oliguria/anuria follows several days later. Although the pathogenesis is unknown, available evidence strongly suggests that endothelial cell damage is necessary.

The outcome for most patients who have D+ HUS is favorable: 65% to 85% recover completely, 5% to 10% die (usually during the acute illness), recurrence is uncommon, and only a few patients slowly progress to end-stage renal disease (ESRD).

VARIANTS

CNS

Acute neurology and neurophysiology of haemolytic-uraemic syndrome.

Eriksson KJ, Boyd SG, Tasker RC.

Tampere University Hospital, Department of Pediatrics, Pediatric Neurology Unit, PO Box 2000, FIN-33521 Tampere, Finland.
Arch Dis Child 2001 May;84(5):434-5 Abstract quote
Involvement of the central nervous system (CNS) is found in around 30% of children with haemolytic-uraemic syndrome (HUS). This complication is the single most common cause of mortality and also a major contributor to the morbidity associated with HUS.

We reviewed 22 children with HUS and acute CNS involvement. Both global and focal derangements occurred, and in survivors, early regional EEG abnormalities-especially those in the occipital and temporal areas-were prognostically useful

Brain involvement in haemolytic-uraemic syndrome: MRI features of coagulative necrosis.

Schmidt S, Gudinchet F, Meagher-Villemure K, Maeder P.

Department of Diagnostic and Interventional Radiology, University Hospital-CHUV, Lausanne, Switzerland.
Neuroradiology 2001 Jul;43(7):581-5 Abstract quote
We describe radiological demonstration of brain involvement in haemolytic-uraemic syndrome (HUS) in two siblings with a very different clinical course.

While the brother presented with a mild, reversible encephalopathy, his sister developed high-signal lesions in the cortex, putamen and caudate nucleus on T1-weighted images, seen as dense areas on CT. Biopsy revealed coagulative necrosis due to microthrombosis without haemorrhage, calcification or infection.

These findings suggest a possible prognostic role for MRI in cases of encephalopathy due to HUS.

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL

VARIANTS

KIDNEYS

Acquired glomerulocystic kidney disease following hemolytic uremic syndrome.

Emma F, Muda AO, Rinaldi S, Boldrini R, Bosman C, Rizzoni G.

Division of Nephrology, Children's Hospital and Research Institute Bambino Gesu', Rome, Italy.
Pediatr Nephrol 2001 Jul;16(7):557-60 Abstract quote
Glomerulocystic kidney disease (GCKD) is a rare congenital condition that is usually reported in infants and young children. Only five cases of acquired GCKD after an acquired renal disease have been reported.

Among these, two patients have developed cystic glomerular lesions following hemolytic uremic syndrome (HUS). We report a third case in a 2-year-old patient with this association. Common features between these three cases include atypical HUS, development of GCKD after prolonged peritoneal dialysis treatment, severe hypertension, and normal-sized kidneys without development of macroscopic cysts. Pathology findings in our patient include heavy expression of epidermal growth factor receptor in proximal tubules and evidence of obstruction of the glomerular outflow.

We speculate that cystic dilatation of the Bowman's capsule may be secondary to ischemic lesions leading to proximal tubular obstruction.

SPECIAL STAINS/IMMUNOPEROXIDASE/
OTHER CHARACTERIZATION

SPECIAL STAINS

IMMUNOPEROXIDASE

Immunohistochemical detection of verotoxin receptors in nervous system.

Utsunomiya I, Ren J, Taguchi K, Ariga T, Tai T, Ihara Y, Miyatake T.

Department of Neuroscience, Showa Pharmaceutical University, 3-3165 Higashitamagawagakuen, Machida, 194-8543, Tokyo, Japan.
Brain Res Brain Res Protoc 2001 Oct;8(2):99-103 Abstract quote
Verotoxin receptor is a globotriaosylceramide (Gb3) present on vascular endothelial cells, in which the toxin causes hemolytic uremic syndrome. We established a sensitive method of immunohistochemical staining in serial sections using monoclonal antibodies (mAbs) against verotoxin and glycolipids that includes Gb3 and galactosylGb3 (GalGb3). With it, we showed co-localization of the verotoxin receptor and Gb3 in dorsal root ganglia (DRG) of humans, rabbits, rats and mice.

We also used a very simple method to identify the presence of lipofuscin-like autofluorescence which complicates fluorescence microscopy observation of aged human nervous tissues.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

THROMBOTIC THROMBOCYTOPENIC PURPURA

Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. A review of 56 autopsy cases.

Hosler GA, Cusumano AM, Hutchins GM.

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Md, USA.

Arch Pathol Lab Med. 2003 Jul;127(7):834-9 Abstract quote
CONTEXT: Thrombotic thrombocytopenic purpura (TTP) and the hemolytic uremic syndrome (HUS) share many clinical features and have been difficult to separate into distinct entities. Histologic examination of organs from autopsied patients suggested that TTP and HUS have dissimilar lesions of different severity and distribution.

OBJECTIVE: To perform a retrospective observational review of autopsied patients with TTP or HUS to compare the nature and severity of the lesions found.

DESIGN: To examine the pathologic features of these conditions, we reviewed all cases among 51 350 indexed autopsies at The Johns Hopkins Hospital (Baltimore, Md) diagnosed with TTP or HUS, and included those showing multiple arteriolar thrombi or their sequela.

RESULTS: The 56 cases that met the inclusion criteria fell into 2 distinct groups, based on distribution and severity of arteriolar lesions. In 25 patients classified as having TTP, platelet-rich thrombi were present-in decreasing severity-in heart, pancreas, kidney, adrenal gland, and brain. In 31 patients with HUS, fibrin/red cell-rich thrombi were present, largely confined to the kidney and often severe, and only 6 cases showed pancreas involvement, 4 adrenal gland involvement, 2 brain involvement, and 1 heart involvement.

CONCLUSION: Despite similar clinical features and therapeutic approaches, TTP and HUS each have a characteristic constellation of histopathologic findings. This observation suggests that TTP and HUS are 2 distinct disease entities with different pathophysiologies, and that they do not represent a spectrum of the same disease process.

Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura.

Ruggenenti P, Noris M, Remuzzi G.

Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Kidney Int 2001 Sep;60(3):831-46 Abstract quote
The term thrombotic microangiopathy (TMA) defines a lesion of vessel wall thickening (mainly arterioles or capillaries), intraluminal platelet thrombosis, and partial or complete obstruction of the vessel lumina.

Depending on whether renal or brain lesions prevail, two pathologically indistinguishable but somehow clinically different entities have been described: the hemolytic uremic syndrome (HUS) and the thrombotic thrombocytopenic purpura (TTP). Injury to the endothelial cell is the central and likely inciting factor in the sequence of events leading to TMA. Loss of physiological thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, abnormal von Willebrand factor release and fragmentation, and increased vascular shear stress may then sustain and amplify the microangiopathic process. Intrinsic abnormalities of the complement system and of the von Willebrand factor pathway may account for a genetic predisposition to the disease that may play a paramount role in particular in familial and recurrent forms. Outcome is usually good in childhood, Shiga toxin-associated HUS, whereas renal and neurological sequelae are more frequently reported in adult, atypical, and familial forms of HUS and in TTP.

Plasma infusion or exchange is the only treatment of proven efficacy. Bilateral nephrectomy and splenectomy may serve as rescue therapies in very selected cases of plasma resistant HUS or recurrent TTP, respectively.

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS): the new thinking.

Liu J, Hutzler M, Li C, Pechet L.

Department of Pathology, University of Massachusetts Memorial Health Care, Worcester, MA 01605, USA.
J Thromb Thrombolysis 2001 May;11(3):261-72 Abstract quote
TTP and HUS are two disorders with many similarities. Though their first descriptions appeared at different time in history, there has been a trend among physicians to consider them as the same clinical entity.

However, in recent years new research findings on the pathophysiology of TTP and HUS have revealed some differences between the two disorders. In this paper, we will review the current approaches to the clinical and laboratory diagnosis of TTP and HUS, as well as therapeutic strategies. We will also summarize the recent advances in three areas in the study of the pathophysiology of TTP and HUS, namely the newly discovered von Willebrand factor multimer-cleaving protease, endothelial cell apoptosis induced by serum from patients with TTP and atypical HUS and the activation of complement system.

Since distinguishing and differentiating between TTP and HUS may help to develop more effective therapies targeted at key steps of the disease development, we will discuss possible ways of reclassifying the TTP-HUS disorders. In the end, we also present our views on possible future development.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSTIC FACTORS

ANTIBIOTIC THERAPY

Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis: a meta-analysis.

Safdar N, Said A, Gangnon RE, Maki DG.

Department of Medicine, University of Wisconsin Medical School and University of Wisconsin Hospital and Clinics, Madison, WI 53792-5158, USA.
JAMA 2002 Aug 28;288(8):996-1001 Abstract quote
CONTEXT: The use of antibiotics for treatment of Escherichia coli O157:H7 infection has become controversial since a recent small study found that it may increase the risk of hemolytic uremic syndrome (HUS). However, other larger studies have reported a protective effect or no association.

OBJECTIVE: To determine whether antibiotic therapy for E coli O157:H7 enteritis increases the risk of HUS.

DATA SOURCES: PubMed and MEDLINE computer searches were performed for studies published from January 1983 to February 2001 using the key words hemolytic uremic syndrome, risk factor, antibiotics, and Escherichia coli O157:H7. Reference lists of relevant publications were reviewed, and 12 experts in the field were contacted to identify additional reports. No language restrictions were applied to the search.

STUDY SELECTION: Studies were included if they reported a series of patients with documented E coli O157:H7 enteritis, some of whom developed HUS; had clear definitions of HUS; and had adequate data delineating the relationship between antibiotic therapy and the occurrence of HUS. Nine of the 26 identified studies fulfilled these criteria.

DATA EXTRACTION: Two authors (N.S. and A.S.) independently reviewed each report identified by the searches and recorded predetermined information relevant to the inclusion criteria. A pooled odds ratio was calculated using a fixed-effects model, with assessment of heterogeneity among the studies.

DATA SYNTHESIS: The pooled odds ratio was 1.15 (95% confidence interval, 0.79-1.68), indicating that there does not appear to be an increased risk of HUS with antibiotic treatment of E coli O157:H7 enteritis. Incomplete reporting of data in individual studies precluded adjustment for severity of illness.

CONCLUSION: Our meta-analysis did not show a higher risk of HUS associated with antibiotic administration. A randomized trial of adequate power, with multiple distinct strains of E coli O157:H7 represented, is needed to conclusively determine whether antibiotic treatment of E coli O157:H7 enteritis increases the risk of HUS.

TREATMENT

APHERESIS

Extracorporeal plasma treatment in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: a review.

Bosch T, Wendler T.

Department of Internal Medicine I, Klinikum Grosshadern, University of Munich, Germany.
Ther Apher 2001 Jun;5(3):182-5 Abstract quote
This review summarizes the state of the art of apheresis in hemolytic uremic syndrome (HUS) and in thrombotic thrombocytopenic purpura (TTP). Both entities are characterized by thrombotic microangiopathy, hemolytic anemia, and thrombocytopenia.

While HUS often presents with renal insufficiency, cerebral involvement is more common in TTP. Recently, in TTP, a primary or secondary lack of activity of a von Willebrand factor (vWF) degrading enzyme was made responsible for the presence of unusually large vWF multimers causing platelet aggregation and thrombus formation in the microvasculature. In contrast, in familial HUS, a factor H deficiency with uninhibited complement activation seems to play a role. Therapeutic plasma exchange (TPE) using fresh frozen plasma or cryosupernatant as the substitution fluid is indicated in acute TTP and atypical HUS without antecedent diarrhea.

As a rule, it will show good effectiveness, especially in the former entity. HUS in pregnancy should be treated by instant delivery whereas postpartum HUS may resolve using protracted courses of TPE. In contrast, in thrombotic microangiopathy after bone marrow transplantation as well as in HUS due to cancer, mitomycin C, or after renal transplantation, TPE is of questionable value and indicated only as a last resort treatment.

TRANSPLANTATION

Combined kidney and liver transplantation for familial haemolytic uraemic syndrome.
Remuzzi G, Ruggenenti P, Codazzi D, Noris M, Caprioli J, Locatelli G, Gridelli B.

Ospedali Riuniti, Bergamo, Italy.
Lancet 2002 May 11;359(9318):1671-2 Abstract quote
Recurrent haemolytic uraemic syndrome (HUS) is a genetic form of thrombotic microangiopathy that is mostly associated with low activity of complement factor H. The disorder usually develops in families, leads to end stage renal disease, and invariably recurs after kidney transplantation.

We did a simultaneous kidney and liver transplantation in a 2-year-old child with HUS and a mutation in complement factor H to restore the defective factor H, with no recurrence of the disease. The operation was successful, and at discharge, the child had healthy kidney and liver function, with no sign of haemolysis.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Weedon D. Weedon's Skin Pathology. Second Edition. Churchill Livingstone. 2002.
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.

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DISEASE ASSOCIATIONS	CHARACTERIZATION
ANTIBIOTICS
Ciprofloxacin-associated hemolytic-uremic syndrome. Allan DS, Thompson CM, Barr RM, Clark WF, Chin-Yee IH. David S Allan MSc MD, Hematology Fellow, University of Western Ontario, London, Ontario, Canada.	Ann Pharmacother 2002 Jun;36(6):1000-2 Abstract quote OBJECTIVE: To report the first case of ciprofloxacin-associated hemolytic-uremic syndrome (HUS). CASE SUMMARY: A 53-year-old white man was treated with chemotherapy for acute lymphoblastic leukemia. Four weeks after initiation of treatment, he recovered his blood cell counts, but developed fever and was prescribed oral ciprofloxacin 500 mg twice daily. After 4 doses, he developed the typical features of HUS manifested by microangiopathic hemolytic anemia, oliguric renal failure, and thrombocytopenia. The medication was withdrawn, and he received 5 sessions of plasma exchange. He recovered completely and has normal renal function. DISCUSSION: Secondary HUS or its related syndrome, thrombotic thrombocytopenic purpura (TTP), is uncommon, but has been reported in association with cancer, chemotherapy, and a variety of medications. Our case represents a possible adverse drug reaction to ciprofloxacin according to the Naranjo probability scale. It is the first reported case of HUS associated with ciprofloxacin. CONCLUSIONS: Ciprofloxacin use was followed by HUS in our patient and was possibly causally related. Early detection, discontinuation of the offending medication, and treatment of HUS/TTP is critical.
CHEMOTHERAPY
Hemolytic uremic syndrome after chemotherapy with gemcitabine and taxotere: a case report. Citarrella P, Gebbia V, Teresi M, Miceli S, Sciortino G, Vaglica M, Pizzardi N, Palmeri S. Division of Oncohematology, University of Palermo, Italy.	Anticancer Res 2002 Mar-Apr;22(2B):1183-5 Abstract quote A case of hemolytic uremic syndrome is reported in a female patient affected by metastatic breast carcinoma receiving chemotherapy with gemcitabine and docetaxel. Up to now this is the first case that has been reported in the medical literature in patients treated with docetaxel (taxotere)and gemcitabine. The patient developed hemolytic uremic syndrome after the third cycle of chemotherapy. She was treated with diuretics, steroids, antibiotics, antifungal drugs, erythropoietin and fluid replacement. The patient underwest dialysis, and survived the hemolytic uremic syndrome. It was not possible to ascertain if the hemolytic uremic syndrome was related to the chemotheraputic treatment or the cancer itself.
HIV
Chronic diarrhea, hemorrhagic colitis, and hemolytic-uremic syndrome associated with HEp-2 adherent Escherichia coli in adults infected with human immunodeficiency virus in Bangui, Central African Republic. Mossoro C, Glaziou P, Yassibanda S, Lan NT, Bekondi C, Minssart P, Bernier C, Le Bouguenec C, Germani Y. Unite des Maladies Infectieuses Opportunistes, Institut Pasteur de Bangui, Central African Republic.	J Clin Microbiol 2002 Aug;40(8):3086-8 Abstract quote In human immunodeficiency virus (HIV)-infected adults from the Central African Republic, the occurrence of chronic diarrhea due to HEp-2 adherent Escherichia coli (EAEC) harboring virulence markers (eaeA, BFP, EAF, astA determinant of EAST/1, positive FAS test, enteropathogenic E. coli O serogroup) was shown to be associated with AIDS. We also show that EAEC that produce verotoxin (Stx2) but do not harbor the genetic markers for classical enterohemorrhagic E. coli are involved in hemorrhagic colitis and hemolytic-uremic syndrome in patients with HIV.
PNEUMOCOCCAL DISEASE
Prognosis of Streptococcus pneumoniae-induced hemolytic uremic syndrome. Nathanson S, Deschenes G. Service de Nephrologie Pediatrique, Hopital Armand-Trousseau, 26 Avenue Arnold-Netter, 75571 Paris, France.	Pediatr Nephrol 2001 Apr;16(4):362-5 Abstract quote Streptococcus pneumoniae-induced hemolytic uremic syndrome (HUS) is known to be a severe acute disease leading to death in one-third of cases, but data regarding the long-term follow-up are lacking. A new series of 11 patients with Streptococcus pneumoniae-induced HUS associated with meningitis and pneumonia constituted a multi-center review. Among 9 patients with a severe acute infectious disease, 3 died from meningitis and 1 from neurological sequelae after a partial recovery of renal function. The mean duration of dialysis was 32 days in patients with acute renal failure who survived the acute infectious period. Cortical necrosis was documented in five of six kidney specimens. Among the 7 surviving patients, 5 developed end-stage renal failure 4-17 years later.
Invasive pneumococcal disease and hemolytic uremic syndrome. Brandt J, Wong C, Mihm S, Roberts J, Smith J, Brewer E, Thiagarajan R, Warady B. Department of Pediatrics, Children's Hospital of New Mexico, Albuquerque, New Mexico 87131-5311, USA.	Pediatrics 2002 Aug;110(2 Pt 1):371-6 Abstract quote OBJECTIVE: Severe pneumococcal infections have been associated with hemolytic uremic syndrome (HUS), usually with a poor clinical outcome when compared with Escherichia coli O157 gastroenteritis-associated (D+) HUS. We examined our experience with 12 cases of Streptococcus pneumoniae-associated HUS (SP-HUS) and compare it with a cohort of diarrhea-associated HUS (D+ HUS). METHODS: A retrospective case survey compared 2 unrelated groups of HUS patients. Demographic factors, clinical indices of disease severity, and outcome were used to compare the 2 groups of HUS patients. RESULTS: Twelve children with SP-HUS were studied. Pneumococcal pneumonia with empyema was the most common precipitating illness (67%), pneumococcal meningitis was present in 17% of children, pneumonia with bacteremia in 8%, and both pneumonia and meningitis in 8%. SP-HUS patients were younger than D+ HUS patients (22.1 vs 49 months) and had more severe renal and hematologic disease than D+ HUS patients. Compared with D+ HUS patients, SP-HUS patients were more likely to require dialysis (75% vs 59%) and had a longer duration of hospitalization (33.2 vs 16.1 days) and duration of thrombocytopenia (11.6 vs 6.8 days). SP-HUS patients were also more likely to require platelet transfusions (83% vs 47%) and needed more platelet (4.7 vs 0.5) and packed red blood cell transfusions (7.8 vs 2.0). The 2 groups did not differ significantly in the incidence of extrarenal HUS complications. There were no deaths in either group. Seven patients have been seen for long-term follow-up; 2 developed end-stage renal disease, and 5 have normal renal function. CONCLUSIONS: HUS is a rare but severe complication of invasive pneumococcal infection. Although disseminated intravascular coagulation can also occur in these children, the treatment and follow-up may be different in the 2 conditions. Children with pneumococcal disease and severe hematologic or renal abnormalities should be investigated for evidence of HUS.

PATHOGENESIS	CHARACTERIZATION
GENERAL	E. coli, Shigella, Salmonella, Yersinia, and Campylobacter species
ANIMAL MODEL
Gnotobiotic piglets develop thrombotic microangiopathy after oral infection with enterohemorrhagic Escherichia coli. Gunzer F, Hennig-Pauka I, Waldmann KH, Sandhoff R, Grone HJ, Kreipe HH, Matussek A, Mengel M. Institute of Medical Microbiology, Hannover Medical School, Germany.	Am J Clin Pathol 2002 Sep;118(3):364-75 Abstract quote Oral infection with enterohemorrhagic Escherichia coli (EHEC) may cause severe enteritis, followed in up to 10% of cases by an extraintestinal complication, the hemolytic uremic syndrome (HUS). HUS is characterized by a triad of symptoms: anemia, thrombocytopenia, and acute renalfailure due to thrombotic microangiopathy. EHEC produces several virulence factors, among which a family of phage-encoded cytotoxins, called Shiga toxin 1 and Shiga toxin 2, seems to be most important. However, since an appropriate animal model is not available, pathogenicity of these emerging enteric pathogens is still poorly understood. Germ-free gnotobiotic piglets infected orally with an O1577:H7 or an O26:H11 EHEC wild-type isolate, both producing Shiga toxin 2, developed intestinal and extraintestinal manifestations of EHEC disease, including thrombotic microangiopathy in the kidneys, the morphologic hallmark of HUS in humans. Thus, gnotobiotic piglets are suitable to further study the pathophysiology of EHEC-induced HUS. It can be expected that data obtainedfrom this animal model will improve our current standard of knowledge about this emerging infectious disease.
BASIC FIBROBLASTIC GROWTH FACTOR
Basic fibroblast growth factor among children with diarrhea-associated hemolytic uremic syndrome. Ray P, Acheson D, Chitrakar R, Cnaan A, Gibbs K, Hirschman GH, Christen E, Trachtman H; The Investigators of the Hemolytic Uremic Syndrome-Synsorb PK Multicenter Clinical Trial. Department of Pediatrics, Children's National Medical Center, Washington, DC, USA	J Am Soc Nephrol 2002 Mar;13(3):699-707 Abstract quote Diarrhea-associated hemolytic uremic syndrome (D+HUS) is characterized by endothelial injury and activation of inflammatory cytokines. Basic fibroblast growth factor (bFGF) is an angiogenic peptide released in response to vascular damage. The plasma concentrations and urinary excretion of bFGF during the course of D+HUS were determined, in comparison with the levels of various inflammatory cytokines, and changes were correlated with clinical and laboratory features of the disease. Serial plasma and urine samples were collected from 31 children with D+HUS, during the acute (days 1 to 7 of hospitalization) and recovery (through day 60 after discharge from the hospital) phases of the disease. The patients were enrolled in the multicenter trial of SYNSORB Pk (SYNSORB Biotech, Calgary, Alberta, Canada) treatment for D+HUS. bFGF, interleukin-1alpha (IL-1alpha), IL-8, and tumor necrosis factor-alpha levels were determined with enzyme-linked immunosorbent assays. bFGF was detected in urine and plasma samples more frequently than were IL-1alpha, IL-8, and tumor necrosis factor-alpha. There was an acute increase in urinary bFGF excretion, which returned to normal during convalescence. Urinary excretion of bFGF during the acute phase was higher among patients who required dialysis, compared with those who did not (48.9 +/- 15.0 and 28.9 +/- 9.0 pg/ml, respectively; P < 0.05). Plasma bFGF concentrations were persistently elevated throughout the period of hospitalization and the follow-up period among patients with D+HUS. Urinary excretion and plasma levels of bFGF were comparable for the SYNSORB Pk-treated (n = 19) and placebo-treated (n = 12) groups. Measurements of urinary and plasma concentrations of bFGF among patients with D+HUS may be useful indices for assessment of the severity of acute renal disease and the timing and adequacy of the systemic angiogenic process during early convalescence.
COMPLEMENT FACTOR H
Complement factor H and hemolytic uremic syndrome. Zipfel PF, Skerka C, Caprioli J, Manuelian T, Neumann HH, Noris M, Remuzzi G. Department of Infection Biology, Hans Knoell Institute for Natural Products Research, Beutenbergstr. I1a, 07745 Jena, Germany.	Int Immunopharmacol 2001 Mar;1(3):461-8 Abstract quote Factor H is a 150 kDa single chain plasma glycoprotein that plays a pivotal role in the regulation of the alternative pathway of complement. Primary sequence analysis reveals a structural organization of this plasma protein, in 20 homologous units, called Short Consensus Repeats (SCRs), each about 60 amino acids long. Biochemical and genetic studies show an association between factor H deficiency and human diseases, including Systemic Lupus Erythematosus, susceptibility to pyogenic infection and a form of membranoproliferative glomerulonephropathy. More recently, factor H deficiency has also been associated with susceptibility to Hemolytic Uremic Syndrome (HUS), a disease consisting of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure, caused by platelet thrombi which mainly, but not exclusively, form in the microcirculation of the kidney. In this review, we summarize recent genetic and biochemical data, which indicate a critical role for factor H in the pathogenesis of HUS and suggest an important role of the most C-terminal domain, i.e. SCR 20, in the disease. In addition, we discuss the physiological consequences of these findings, as novel functional data show a particular essential role of SCR 20 of factor H as the central discriminatory and regulatory site of this multidomain, multifunctional plasma protein.
E. COLI 0157:H7
Regulation of virulence factors of enterohemorrhagic Escherichia coli O157:H7 by self-produced extracellular factors. Kanamaru K, Kanamaru K, Tatsuno I, Tobe T, Sasakawa C. Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan.	Biosci Biotechnol Biochem 2000 Nov;64(11):2508-11 Abstract quote Enterohemorrhagic Escherichia coli (EHEC) O157:H7 causes serious diarrhea and hemolytic uremic syndrome in humans. The expressions of EspD and intimin by O157:H7 have now been shown to be down-regulated by medium conditioned by O157:H7 grown at stationary phase. Preparation of conditioned medium showing the effect on the amount of EspD was not dependent on temperature or growth medium, but was dependent on growth phase. Inhibition of EspD and intimin expression was also induced by medium conditioned by E. coli K-12 strains and homoserine lactone, a signal molecule of the quorum-sensing system in gram-negative bacteria. These results suggest the possibility that the quorum-sensing system mediated by self-produced extracellular factors plays an important role in control of colonization of EHEC O157:H7.
Complete genome sequence of enterohemorrhagic Escherichia coli O157:H7 and genomic comparison with a laboratory strain K-12. Hayashi T, Makino K, Ohnishi M, Kurokawa K, Ishii K, Yokoyama K, Han CG, Ohtsubo E, Nakayama K, Murata T, Tanaka M, Tobe T, Iida T, Takami H, Honda T, Sasakawa C, Ogasawara N, Yasunaga T, Kuhara S, Shiba T, Hattori M, Shinagawa H. Department of Microbiology, Miyazaki Medical College, Kiyotake, Japan.	DNA Res 2001 Feb 28;8(1):11-22 Abstract quote Escherichia coli O157:H7 is a major food-borne infectious pathogen that causes diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome. Here we report the complete chromosome sequence of an O157:H7 strain isolated from the Sakai outbreak, and the results of genomic comparison with a benign laboratory strain, K-12 MG1655. The chromosome is 5.5 Mb in size, 859 Kb larger than that of K-12. We identified a 4.1-Mb sequence highly conserved between the two strains, which may represent the fundamental backbone of the E. coli chromosome. The remaining 1.4-Mb sequence comprises of O157:H7-specific sequences, most of which are horizontally transferred foreign DNAs. The predominant roles of bacteriophages in the emergence of O157:H7 is evident by the presence of 24 prophages and prophage-like elements that occupy more than half of the O157:H7-specific sequences. The O157:H7 chromosome encodes 1632 proteins and 20 tRNAs that are not present in K-12. Among these, at least 131 proteins are assumed to have virulence-related functions. Genome-wide codon usage analysis suggested that the O157:H7-specific tRNAs are involved in the efficient expression of the strain-specific genes. A complete set of the genes specific to O157:H7 presented here sheds new insight into the pathogenicity and the physiology of O157:H7, and will open a way to fully understand the molecular mechanisms underlying the O157:H7 infection.
ENDOTHELIUM
The role of the endothelium in hemolytic uremic syndrome. Zoja C, Morigi M, Remuzzi G. Mario Negri Institute for Pharmacological Research, Bergamo, Italy.	J Nephrol 2001 Nov-Dec;14 Suppl 4:S58-62 Abstract quote Hemolytic uremic syndrome (HUS), which is the most common cause of acute renal failure in children, is caused by Shiga toxin-producing Escherichia coli infection. This infection leads to renal and other organ microvascular thrombosis. Endothelial injury has been recognized as the trigger event in the development of microangiopathic process. Evidence suggests that leukocyte as well as platelet activation participate in endothelial damage. Intrinsic abnormalities of the complement system may also play a role in HUS.
TOXINS	Shiga and Shigalike toxins, produced by some strains of Shigella dysenteriae and E coli 0157:H7 70% of cases of HUS in children
Pathogenesis of Shiga toxin-induced hemolytic uremic syndrome. Ray PE, Liu XH. Children's Research Institute, Research Center for Molecular Physiology, Washington, DC, USA.	Pediatr Nephrol 2001 Oct;16(10):823-39 Abstract quote The term hemolytic uremic syndrome (HUS) was first introduced to describe a heterogeneous group of diseases characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Substantial progress has been made in our understanding of the etiology and pathogenesis of HUS. This article reviews some of the classic and new concepts related to the pathogenesis of Shiga toxin (Stx)-HUS and discusses their clinical relevance for the diagnosis and treatment of this syndrome. Infection with Stx-producing bacteria can induce HUS after a prodromal illness with or without diarrhea. Stx-induced renal endothelial injury is the primary pathogenic event. However, Stx also damages mesangial cells, as well as glomerular and renal tubular epithelial cells. Young children are at greatest risk for Stx-HUS because they express high levels of Stx receptors in renal glomeruli. Older children and adults express lower levels of glomerular Stx receptors and may develop Stx-HUS whenever the combined effects of lipopolysaccharide and cytokines upregulate the expression of Stx receptors and sensitize glomerular endothelial cells to Stx-induced injury, activate the coagulation-fibrinolytic system, and induce endothelial injury. Chemokine receptors and cytokines released by inflammatory cells (i.e., monocyte chemoattractant protein-1, interleukin-6, interleukin-8,) or injured endothelial cells (i.e., basic fibrobast growth factor) may play roles in this process. Measurement of the activity of a von Willebrand factor protease in plasma may help distinguish patients with thrombotic thrombocytopenic purpura from those with Stx-HUS.
von WILLEBRAND FACTOR-CLEAVING PROTEASE
Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Veyradier A, Obert B, Houllier A, Meyer D, Girma JP. INSERM Unite 143, Le Kremlin Bicetre, France.	Blood 2001 Sep 15;98(6):1765-72 Abstract quote Retrospective studies of patients with thrombotic microangiopathies (TMAs) have shown that a deficient activity of von Willebrand factor (vWF)-cleaving protease is involved in thrombotic thrombocytopenic purpura (TTP) but not in the hemolytic-uremic syndrome (HUS). To further analyze the relevance of this enzymatic activity in TMA diagnosis, a 20-month multicenter study of vWF-cleaving protease activity was conducted in adult patients prospectively enrolled in the acute phase of TMA. Patients with sporadic (n = 85), intermittent (n = 21), or familial recurrent (n = 5) forms of TMA (66 manifesting as TTP and 45 as HUS) were included. TMA was either idiopathic (n = 42) or secondary to an identified clinical context (n = 69). vWF-cleaving protease activity was normal in 46 cases (7 TTP and 39 HUS) and decreased in 65 cases (59 TTP and 6 HUS). A protease inhibitor was detected in 31 cases and was observed only in patients manifesting TTP with a total absence of protease activity. Among the 111 patients, mean vWF antigen levels were increased and the multimeric distribution of vWF was very heterogeneous, showing either a defect of the high-molecular-weight forms (n = 40), a normal pattern (n = 21), or the presence of unusually large multimers (n = 50). Statistical analysis showed that vWF-protease deficiency was associated with the severity of thrombocytopenia (P <.01). This study emphasizes that vWF-cleaving protease deficiency specifically concerns a subgroup of TMA corresponding to the TTP entity.
Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Furlan M, Lammle B. Central Hematology Laboratory, University Hospital, Inselspital, Bern, Switzerland.	Best Pract Res Clin Haematol 2001 Jun;14(2):437-54 Abstract quote Thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS) are today often regarded as variants of one syndrome denoted as TTP/HUS, characterized by thrombocytopenia caused by intravascular platelet clumping, microangiopathic haemolytic anaemia, fever, renal abnormalities and neurological disturbances. Unusually large von Willebrand factor multimers have been observed in plasma from patients with chronic relapsing forms of TTP. Their appearance in patients with classic TTP is caused by deficiency of a specific von Willebrand factor-cleaving protease. A constitutional deficiency of this protease has consistently been found in familial cases of TTP, whereas in acquired TTP the protease deficiency is caused by the presence of an inhibiting autoantibody. A normal activity of von Willebrand factor-cleaving protease has been established in patients with HUS. In this chapter, we report 23 cases with severe constitutional protease deficiency: about one half of these patients had their first acute episode as children, whereas the other half had their first TTP event at an adult age, several of them during their first pregnancy. Two of these 23 individuals with congenital protease deficiency, both older than 35 years, have never had an acute TTP event. These results indicate that a deficiency of von Willebrand factor-cleaving protease alone is not sufficient to cause acute TTP. Patients with long-lasting dormant protease deficiency have been found to experience multiple relapses of TTP after having had their first acute episode. In one protease-deficient, plasma-dependent patient with chronic relapsing TTP, we estimated that 5% of normal protease activity is sufficient to remove the most adhesive von Willebrand factor multimers and prevent the formation of platelet microthrombi. The deficiency of von Willebrand factor-cleaving protease is a very strong risk factor for TTP, but the development of an acute bout requires a trigger, possibly causing the activation or apoptosis of endothelial cells in the microcirculation. It is unclear whether anti-endothelial cell antibodies, cytokines or other agents are involved in triggering thrombotic microangiopathy. The release of platelet calpain (and/or other proteases), leading to a degradation of von Willebrand factor and to platelet aggregation, has been reported in patients during their acute TTP episode. It is unknown whether calpain directly triggers an acute event or whether it merely reflects its release during the aggregation of platelets by the unusually large von Willebrand factor multimers. With regard to the heterogeneous aetiology of thrombotic microangiopathies, requiring distinct therapeutic measures, a new classification of thrombotic microangiopathy should replace the current, frequently inappropriate clinical discrimination between TTP and haemolytic uraemic syndrome.

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
Changes of renal flow volume in the hemolytic-uremic syndrome--color Doppler sonographic investigations. Scholbach TM. KinderKlinik St. Georg, Leipzig, Germany.	Pediatr Nephrol 2001 Aug;16(8):644-7 Abstract quote Varying degrees of vascular occlusion can be found in the hemolytic-uremic syndrome (HUS). This is the rationale for Doppler sonographic investigations of renal blood flow in children with HUS. In 1989 a first report suggested a close relationship between normalization of the resistive index (RI) of renal blood flow with the restitution of urine flow in affected children. Later reports did not confirm these initial findings. The aim of this paper is to describe renal volume perfusion quantitatively in children with HUS. The renal arteries in 35 patients with HUS (1 month to 15 years) were investigated at the onset of HUS by color Doppler ultrasonography. Flow volume measurements were carried out in the 1st week and in the 2nd to 4th week after onset of the disease. These data were compared with measurements from a healthy pediatric population of 69 children. Statistically significant changes in renal perfusion occur in the flow volume of the kidneys. The flow volume dropped to 32% (34%) in the 1st week of the disease compared with the normal population and recovered in 2-4 weeks to 117% (65%) of the normal flow volume (left kidney in parentheses). The new technique of volumetric perfusion measurement overcomes some drawbacks of the traditional RI, which may have led to some confusion in the past.
LABORATORY MARKERS
LEUKOCYTOSIS
LEUKOCYTOSIS
Leukocytosis in children with Escherichia coli O157:H7 enteritis developing the hemolytic-uremic syndrome. Buteau C, Proulx F, Chaibou M, Raymond D, Clermont MJ, Mariscalco MM, Lebel MH, Seidman E. Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Quebec, Canada.	Pediatr Infect Dis J 2000 Jul;19(7):642-7 Abstract quote BACKGROUND: Fewer than 10% of children with Escherichia coli O157:H7 enteritis develop hemolytic-uremic syndrome (HUS). OBJECTIVE: To determine whether circulating leukocytes are independent risk markers of developing HUS during E. coli O157:H7 enteritis. METHODS: We reviewed the charts of all children with culture-proved E. coli O157:H7 infections seen at Sainte-Justine Hospital between 1987 and 1997. Epidemiologic data, laboratory indices and circulating leukocytes counts were noted. HUS diagnosis was validated with independent HUS patient lists from the pediatric nephrology services of tertiary care hospitals in the Montreal metropolitan area. The date of onset of enteritis was determined by two independent observers. Leukocyte counts were compared among the following independent groups: (1) uncomplicated O157:H7 enteritis (Group 1); (2) O157:H7 enteritis with the subsequent development of HUS (Group 2); (3) HUS already present at the time of medical consultation (Group 3). RESULTS: There were 369 children with E. coli O157:H7 infection. A complete blood count was not performed in 114 (31%) patients. Observers disagreed on the date of onset of gastroenteritis in 34 (9%) children only (kappa 0.92). The study population thus included 221 patients: Group 1, n = 161; Group 2, n = 27; and Group 3, n = 33. Patients developing HUS (Group 2) presented greater total leukocyte (P < 0.008), polymorphonuclear (P < 0.008) and monocyte (P < 0.07) counts than those with an uncomplicated course (Group 1). Logistic regression analysis showed that young age [odds ratio (OR), 0.98; 95% confidence interval (CI), 0.96 to 0.99], duration of enteric prodrome < or =3 days (OR 4.8, 95% CI 1.13 to 20.7) and initial leukocytosis (OR 1.22, 95% CI, 1.11 to 1.35) were independent predictors of HUS. CONCLUSIONS: Based on the variables identified above, further studies are needed to determine whether the inflammatory response of the host represents only a marker of the severity of gastrointestinal infection or whether, alternatively, it is a pathophysiologic factor that leads to HUS.
PHAGE TYPING
Phage typing and DNA-based comparison of strains of enterohemorrhagic Escherichia coli O157 from apparently sporadic infections in Osaka City, Japan, 1996. Nishikawa Y, Hase A, Ogasawara J, Cheasty T, Willshaw GA, Smith HR, Tatsumi Y, Yasukawa A. Department of Epidemiology, Osaka City Institute of Public Health and Environmental Sciences, Osaka 543-0026, Japan	Jpn J Infect Dis 2001 Aug;54(4):140-3 Abstract quote A marked increase in sporadic cases of enteritis due to enterohemorrhagic Escherichia coli serogroup O157 occurred in Osaka City, Japan, during 1996. To elucidate why the number of cases had increased, the isolates were classified using phage typing, random amplified polymorphic DNA analysis, and pulsed-field gel electrophoresis (PFGE). Fifty-seven percent of the isolates (105/184) belonged to the same phage type (PT-32) and gave the same PFGE pattern; the clone had been isolated during a 3-week period, with a peak on July 15. It was concluded that the majority of the cases identified in July 1996 formed an outbreak, although epidemiological links to a possible common source were not established. The possibility that this outbreak was part of a huge regional outbreak including children at primary schools in Sakai City was discussed.
TISSUE FACTOR
Elevated tissue factor circulating levels in children with hemolytic uremic syndrome caused by verotoxin-producing E. coli. Kamitsuji H, Nonami K, Murakami T, Ishikawa N, Nakayama A, Umeki Y. Department of Pediatrics, Nara Prefectural Nara Hospital, Hiramatsu, Japan.	Clin Nephrol 2000 May;53(5):319-24 Abstract quote BACKGROUND: Microvascular thrombosis in the kidney plays an important role in the pathogenesis of hemolytic uremic syndrome (HUS). Tissue factor (TF), present on the vascular surface of endothelial cells, binds factor VIIa. The complex initiates the coagulating cascade by activating factors X and IX. PATIENTS AND METHODS: In cases of HUS associated with verotoxin-producing E. coli (VTEC) infection, VTEC gastroenteritis without HUS and normal controls, we measured plasma concentrations of TF and tissue factor pathway inhibitor (TFPI) to evaluate their clinical significance. In children with non-HUS chronic renal failure (CRF), the TF levels were also measured as another control group. RESULTS: In the acute phase of HUS, plasma levels of TF and TFPI were significantly elevated, then returned to normal range in the recovery phase. The TF levels were closely correlated with the thrombin antithrombin-III complex, a marker of thrombin activity in circulating blood, and with creatinine clearance (Ccr). Furthermore, a positive correlation was noted between plasma TF levels and plasma soluble thrombomodulin (sTM) levels, which is a marker of endothelial cell injury. The influence of decreased excretion from damaged kidneys should be considered since a definite lot correlation was observed between plasma TF levels and Ccr in children with non-HUS CRF. CONCLUSION: From these findings, we concluded that elevated TF circulating levels may also play an important role in blood-clotting activation observed in VTEC-HUS patients, and may also be a useful marker for renal damage.
von WILLEBRAND FACTOR-CLEAVING PROTEASE
Assays of von Willebrand factor- cleaving protease: a test for diagnosis of familial and acquired thrombotic thrombocytopenic purpura. Furlan M, Lammle B. Central Hematology Laboratory, University Hospital, Inselspital, Bern, Switzerland.	Semin Thromb Hemost 2002 Apr;28(2):167-72 Abstract quote Endothelial cells secrete von Willebrand factor (vWF) multimers that are larger than those found in the circulating plasma. These very large multimeric forms of vWF, capable of spontaneously binding to and agglutinating the blood platelets under conditions of high fluid shear rate, are degraded by a specific metalloprotease cleaving the peptide bond 842Tyr-843Met of the vWF subunit. The vWF-cleaving protease was found to be deficient in patients with familial thrombotic thrombocytopenic purpura (TTP). The acute events in these patients can be successfully treated and prophylactically prevented by repletion of the missing protease using fresh frozen plasma (FFP). In another, apparently more common, form of TTP, the protease deficiency is due to inhibiting circulating antibodies directed against the vWF-cleaving protease. Therapy of these patients should include immunosuppressive treatment in addition to plasma exchange and replacement with FFP. Normal activity of vWF-cleaving protease was established in patients with a clinically similar disorder: hemolytic-uremic syndrome (HUS). The level of vWF-cleaving protease activity is thus a laboratory parameter that provides important information for the differential diagnosis and treatment of patients with TTP/HUS. Several assays of vWF-cleaving protease have been described and are summarized here.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
The United States National Prospective Hemolytic Uremic Syndrome Study: microbiologic, serologic, clinical, and epidemiologic findings. Banatvala N, Griffin PM, Greene KD, Barrett TJ, Bibb WF, Green JH, Wells JG; Hemolytic Uremic Syndrome Study Collaborators. Foodborne and Diarrheal Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.	J Infect Dis 2001 Apr 1;183(7):1063-70 Abstract quote The frequency of Shiga toxin-producing Escherichia coli (STEC) serotypes associated with postdiarrheal hemolytic uremic syndrome (HUS) cases among children and adults in the United States and the proportion with IgM or IgG lipopolysaccharide antibodies to E. coli O157 were determined by use of a nationwide sample from January 1987 through December 1991. Among 83 patients, STEC were isolated from 30 (43%) of 70 whose stool cultures yielded bacterial growth (25 E. coli O157 isolates and 5 non-O157 STEC isolates). Fifty-three (80%) of 66 patients with serum samples had positive O157 lipopolysaccharide antibody titers. Of the 83 patients, 60 (72%) had evidence of STEC infection, including 6 of 8 adults whose illnesses also met criteria for thrombotic thrombocytopenic purpura. Data from a subset of patients suggest that E. coli O157 was the cause of > or = 80% of the STEC infections. All 3 women who were postpartum had evidence of E. coli O157 infection. STEC infection should be considered the likely cause for all persons with postdiarrheal HUS.
Hemolytic-uremic syndrome. Corrigan JJ Jr, Boineau FG.	Pediatr Rev 2001 Nov;22(11):365-9 Abstract quote The hemolytic-uremic syndrome (HUS) has been recognized for more than 45 years and consists of the combination of hemolytic anemia, thrombocytopenia, and acute renal failure. HUS occurs predominantly in children younger than 4 years of age. It is the most frequent cause of acute renal failure in children. The most common form of the syndrome (D+ HUS) occurs in healthy young children (>6 mo to <5 y of age) and is preceded by watery diarrhea that can evolve to hemorrhagic colitis. The diarrhea precedes the hemolysis and thrombocytopenia by 5 to 7 days; oliguria/anuria follows several days later. Although the pathogenesis is unknown, available evidence strongly suggests that endothelial cell damage is necessary. The outcome for most patients who have D+ HUS is favorable: 65% to 85% recover completely, 5% to 10% die (usually during the acute illness), recurrence is uncommon, and only a few patients slowly progress to end-stage renal disease (ESRD).
VARIANTS
CNS
Acute neurology and neurophysiology of haemolytic-uraemic syndrome. Eriksson KJ, Boyd SG, Tasker RC. Tampere University Hospital, Department of Pediatrics, Pediatric Neurology Unit, PO Box 2000, FIN-33521 Tampere, Finland.	Arch Dis Child 2001 May;84(5):434-5 Abstract quote Involvement of the central nervous system (CNS) is found in around 30% of children with haemolytic-uraemic syndrome (HUS). This complication is the single most common cause of mortality and also a major contributor to the morbidity associated with HUS. We reviewed 22 children with HUS and acute CNS involvement. Both global and focal derangements occurred, and in survivors, early regional EEG abnormalities-especially those in the occipital and temporal areas-were prognostically useful
Brain involvement in haemolytic-uraemic syndrome: MRI features of coagulative necrosis. Schmidt S, Gudinchet F, Meagher-Villemure K, Maeder P. Department of Diagnostic and Interventional Radiology, University Hospital-CHUV, Lausanne, Switzerland.	Neuroradiology 2001 Jul;43(7):581-5 Abstract quote We describe radiological demonstration of brain involvement in haemolytic-uraemic syndrome (HUS) in two siblings with a very different clinical course. While the brother presented with a mild, reversible encephalopathy, his sister developed high-signal lesions in the cortex, putamen and caudate nucleus on T1-weighted images, seen as dense areas on CT. Biopsy revealed coagulative necrosis due to microthrombosis without haemorrhage, calcification or infection. These findings suggest a possible prognostic role for MRI in cases of encephalopathy due to HUS.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
THROMBOTIC THROMBOCYTOPENIC PURPURA
Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. A review of 56 autopsy cases. Hosler GA, Cusumano AM, Hutchins GM. Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Md, USA.	Arch Pathol Lab Med. 2003 Jul;127(7):834-9 Abstract quote CONTEXT: Thrombotic thrombocytopenic purpura (TTP) and the hemolytic uremic syndrome (HUS) share many clinical features and have been difficult to separate into distinct entities. Histologic examination of organs from autopsied patients suggested that TTP and HUS have dissimilar lesions of different severity and distribution. OBJECTIVE: To perform a retrospective observational review of autopsied patients with TTP or HUS to compare the nature and severity of the lesions found. DESIGN: To examine the pathologic features of these conditions, we reviewed all cases among 51 350 indexed autopsies at The Johns Hopkins Hospital (Baltimore, Md) diagnosed with TTP or HUS, and included those showing multiple arteriolar thrombi or their sequela. RESULTS: The 56 cases that met the inclusion criteria fell into 2 distinct groups, based on distribution and severity of arteriolar lesions. In 25 patients classified as having TTP, platelet-rich thrombi were present-in decreasing severity-in heart, pancreas, kidney, adrenal gland, and brain. In 31 patients with HUS, fibrin/red cell-rich thrombi were present, largely confined to the kidney and often severe, and only 6 cases showed pancreas involvement, 4 adrenal gland involvement, 2 brain involvement, and 1 heart involvement. CONCLUSION: Despite similar clinical features and therapeutic approaches, TTP and HUS each have a characteristic constellation of histopathologic findings. This observation suggests that TTP and HUS are 2 distinct disease entities with different pathophysiologies, and that they do not represent a spectrum of the same disease process.
Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Ruggenenti P, Noris M, Remuzzi G. Mario Negri Institute for Pharmacological Research, Bergamo, Italy.	Kidney Int 2001 Sep;60(3):831-46 Abstract quote The term thrombotic microangiopathy (TMA) defines a lesion of vessel wall thickening (mainly arterioles or capillaries), intraluminal platelet thrombosis, and partial or complete obstruction of the vessel lumina. Depending on whether renal or brain lesions prevail, two pathologically indistinguishable but somehow clinically different entities have been described: the hemolytic uremic syndrome (HUS) and the thrombotic thrombocytopenic purpura (TTP). Injury to the endothelial cell is the central and likely inciting factor in the sequence of events leading to TMA. Loss of physiological thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, abnormal von Willebrand factor release and fragmentation, and increased vascular shear stress may then sustain and amplify the microangiopathic process. Intrinsic abnormalities of the complement system and of the von Willebrand factor pathway may account for a genetic predisposition to the disease that may play a paramount role in particular in familial and recurrent forms. Outcome is usually good in childhood, Shiga toxin-associated HUS, whereas renal and neurological sequelae are more frequently reported in adult, atypical, and familial forms of HUS and in TTP. Plasma infusion or exchange is the only treatment of proven efficacy. Bilateral nephrectomy and splenectomy may serve as rescue therapies in very selected cases of plasma resistant HUS or recurrent TTP, respectively.
Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS): the new thinking. Liu J, Hutzler M, Li C, Pechet L. Department of Pathology, University of Massachusetts Memorial Health Care, Worcester, MA 01605, USA.	J Thromb Thrombolysis 2001 May;11(3):261-72 Abstract quote TTP and HUS are two disorders with many similarities. Though their first descriptions appeared at different time in history, there has been a trend among physicians to consider them as the same clinical entity. However, in recent years new research findings on the pathophysiology of TTP and HUS have revealed some differences between the two disorders. In this paper, we will review the current approaches to the clinical and laboratory diagnosis of TTP and HUS, as well as therapeutic strategies. We will also summarize the recent advances in three areas in the study of the pathophysiology of TTP and HUS, namely the newly discovered von Willebrand factor multimer-cleaving protease, endothelial cell apoptosis induced by serum from patients with TTP and atypical HUS and the activation of complement system. Since distinguishing and differentiating between TTP and HUS may help to develop more effective therapies targeted at key steps of the disease development, we will discuss possible ways of reclassifying the TTP-HUS disorders. In the end, we also present our views on possible future development.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis and Treatment
Commonly Used Terms

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	HUS
INCIDENCE	Most common cause of acute renal failure in children
Nationwide study of haemolytic uraemic syndrome: clinical, microbiological, and epidemiological features. Elliott EJ, Robins-Browne RM, O'Loughlin EV, Bennett-Wood V, Bourke J, Henning P, Hogg GG, Knight J, Powell H, Redmond D; Contributors to the Australian Paediatric Surveillance Unit. Department of Paediatrics and Child Health, University of Sydney and The Children's Hospital at Westmead, Sydney, Australia	Arch Dis Child 2001 Aug;85(2):125-31 Abstract quote AIMS: To establish the incidence and aetiology of haemolytic uraemic syndrome (HUS) in Australia and compare clinical and microbial characteristics of sporadic and outbreak cases. METHODS: National active surveillance through the Australian Paediatric Surveillance Unit with monthly case notification from paediatricians, July 1994 to June 1998. Children under 15 years presenting with microangiopathic haemolytic anaemia, thrombocytopenia, and acute renal impairment were identified. RESULTS: Ninety eight cases were identified (incidence 0.64 per 10(5) children <15 years/annum and 1.35 per 10(5) children <5 years/annum). Eighty four were associated with diarrhoea (64 sporadic, 20 constituting an outbreak) and 14 were atypical. Shiga toxin producing Escherichia coli (STEC) O111:H- was the most common isolate in sporadic HUS and caused the outbreak. However O111:H- isolates from outbreak and sporadic cases differed in phage type and subtyping by DNA electrophoresis. STEC isolates from sporadic cases included O26:H-, O113:H21, O130:H11, OR:H9, O157:H-, ONT:H7, and ONT:H-. STEC O157:H7 was not isolated from any case. Only O111:H- isolates produced both Shiga toxins 1 and 2 and possessed genes encoding E coli attaching and effacing gene (intimin) and enterohemolysin. Outbreak cases had worse gastrointestinal and renal disease at presentation and more extrarenal complications. CONCLUSIONS: Linking national surveillance with a specialised laboratory service allowed estimation of HUS incidence and provided information on its aetiology. In contrast to North America, Japan, and the British Isles, STEC O157:H7 is rare in Australia; however, non-O157:H7 STEC cause severe disease including outbreaks. Disease severity in outbreak cases may relate to yet unidentified virulence factors of the O111:H- strain isolated.
Growth and survival of Escherichia coli O157: H7 in meat, poultry and vegetables mixed with different concentrations of mayonnaise. Arias ML, Monge-Rojas R, Antillon F, Chaves C. Facultad de Microbiologia, Universidad de Costa Rica, 2060 San Jose, Costa Rica.	Rev Biol Trop 2001 Sep-Dec;49(3-4):1207-12 Abstract quote In the last 20 years Escherichia coli O157: H7 has emerged as a new pathogen, causing worldwide disease, death and economic loss. Different studies have revealed important survival characteristics of this pathogen, although there are divergent criteria about its ability to survive in various mayonnaise formulations. We studied the effect of different mayonnaise concentrations (0%, 18%, 37% and 56%) (weight/weight) over the survival of the bacterium in common foods from a neotropical environment (Costa Rica). High [10(7)-10(8) Colony Forming Units (CFU)/ml] and low E. coli populations (10(4)-10(6) CFU/ml) were inoculated, (three replicates) in meat, chopped cabbage and poultry, and mixed with commercial mayonnaise to obtain the concentrations specified. They were incubated at 12 degrees C for 24, 48 and 72 hr. The E. coli O157: H7 enumeration was done according to a standard methodology. Populations of E. coli O157: H7 showed an increasing trend during the first incubation period (48 hr), in all the preparations, regardless of the fat concentration used. Our data indicate that E. coli O157: H7 is capable of surviving and growing in meat, cabbage and poultry mixed with mayonnaise, independently of its concentration.
Population-based trends in pediatric hemolytic uremic syndrome in California, 1994-1999: substantial underreporting and public health implications. Cummings KC, Mohle-Boetani JC, Werner SB, Vugia DJ. Disease Investigations and Surveillance Branch, Division of Communicable Disease Control, California Department of Health Services, Berkeley 94704, USA.	Am J Epidemiol 2002 May 15;155(10):941-8 Abstract quote This paper describes the epidemiology of childhood hemolytic uremic syndrome (HUS) in California, for which hospitalization data were used, and the proportion of cases reported to public health authorities. HUS discharge data for children < or =17 years of age were extracted from the population-based California Patient Discharge Data Set for 1994-1999 and were linked electronically with HUS reports to public health authorities. Incidence rates per 100,000 children were calculated. The authors identified 585 HUS hospitalizations; 369 were incident cases. The average HUS incidence rate was 0.67 (95% confidence interval: 0.61, 0.74); rates rose modestly from 1994 (0.59, 95% confidence interval: 0.44, 0.78) to 1997 (0.80, 95% confidence interval: 0.63, 10.0) and decreased modestly thereafter (0.59, 95% confidence interval: 0.45, 0.77). Rates were highest for northern California children < or =5 years of age (1.85, 95% confidence interval: 1.55, 2.19). The hospital case-fatality rate was 2.7% (95% confidence interval: 1.1, 4.4); the median charge was $39,500 per child. Only 43.9% of HUS cases in the California Patient Discharge Data Set were reported to public health authorities. Despite heightened efforts to control Shiga toxin-producing Escherichia coli exposures (the predominant cause of childhood HUS in the United States), HUS incidence rates remained relatively stable in California. Reporting HUS cases to public health authorities is important for disease control.

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
VARIANTS
KIDNEYS
Acquired glomerulocystic kidney disease following hemolytic uremic syndrome. Emma F, Muda AO, Rinaldi S, Boldrini R, Bosman C, Rizzoni G. Division of Nephrology, Children's Hospital and Research Institute Bambino Gesu', Rome, Italy.	Pediatr Nephrol 2001 Jul;16(7):557-60 Abstract quote Glomerulocystic kidney disease (GCKD) is a rare congenital condition that is usually reported in infants and young children. Only five cases of acquired GCKD after an acquired renal disease have been reported. Among these, two patients have developed cystic glomerular lesions following hemolytic uremic syndrome (HUS). We report a third case in a 2-year-old patient with this association. Common features between these three cases include atypical HUS, development of GCKD after prolonged peritoneal dialysis treatment, severe hypertension, and normal-sized kidneys without development of macroscopic cysts. Pathology findings in our patient include heavy expression of epidermal growth factor receptor in proximal tubules and evidence of obstruction of the glomerular outflow. We speculate that cystic dilatation of the Bowman's capsule may be secondary to ischemic lesions leading to proximal tubular obstruction.

SPECIAL STAINS/IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS
IMMUNOPEROXIDASE
Immunohistochemical detection of verotoxin receptors in nervous system. Utsunomiya I, Ren J, Taguchi K, Ariga T, Tai T, Ihara Y, Miyatake T. Department of Neuroscience, Showa Pharmaceutical University, 3-3165 Higashitamagawagakuen, Machida, 194-8543, Tokyo, Japan.	Brain Res Brain Res Protoc 2001 Oct;8(2):99-103 Abstract quote Verotoxin receptor is a globotriaosylceramide (Gb3) present on vascular endothelial cells, in which the toxin causes hemolytic uremic syndrome. We established a sensitive method of immunohistochemical staining in serial sections using monoclonal antibodies (mAbs) against verotoxin and glycolipids that includes Gb3 and galactosylGb3 (GalGb3). With it, we showed co-localization of the verotoxin receptor and Gb3 in dorsal root ganglia (DRG) of humans, rabbits, rats and mice. We also used a very simple method to identify the presence of lipofuscin-like autofluorescence which complicates fluorescence microscopy observation of aged human nervous tissues.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
ANTIBIOTIC THERAPY
Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 enteritis: a meta-analysis. Safdar N, Said A, Gangnon RE, Maki DG. Department of Medicine, University of Wisconsin Medical School and University of Wisconsin Hospital and Clinics, Madison, WI 53792-5158, USA.	JAMA 2002 Aug 28;288(8):996-1001 Abstract quote CONTEXT: The use of antibiotics for treatment of Escherichia coli O157:H7 infection has become controversial since a recent small study found that it may increase the risk of hemolytic uremic syndrome (HUS). However, other larger studies have reported a protective effect or no association. OBJECTIVE: To determine whether antibiotic therapy for E coli O157:H7 enteritis increases the risk of HUS. DATA SOURCES: PubMed and MEDLINE computer searches were performed for studies published from January 1983 to February 2001 using the key words hemolytic uremic syndrome, risk factor, antibiotics, and Escherichia coli O157:H7. Reference lists of relevant publications were reviewed, and 12 experts in the field were contacted to identify additional reports. No language restrictions were applied to the search. STUDY SELECTION: Studies were included if they reported a series of patients with documented E coli O157:H7 enteritis, some of whom developed HUS; had clear definitions of HUS; and had adequate data delineating the relationship between antibiotic therapy and the occurrence of HUS. Nine of the 26 identified studies fulfilled these criteria. DATA EXTRACTION: Two authors (N.S. and A.S.) independently reviewed each report identified by the searches and recorded predetermined information relevant to the inclusion criteria. A pooled odds ratio was calculated using a fixed-effects model, with assessment of heterogeneity among the studies. DATA SYNTHESIS: The pooled odds ratio was 1.15 (95% confidence interval, 0.79-1.68), indicating that there does not appear to be an increased risk of HUS with antibiotic treatment of E coli O157:H7 enteritis. Incomplete reporting of data in individual studies precluded adjustment for severity of illness. CONCLUSION: Our meta-analysis did not show a higher risk of HUS associated with antibiotic administration. A randomized trial of adequate power, with multiple distinct strains of E coli O157:H7 represented, is needed to conclusively determine whether antibiotic treatment of E coli O157:H7 enteritis increases the risk of HUS.
TREATMENT
APHERESIS
Extracorporeal plasma treatment in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: a review. Bosch T, Wendler T. Department of Internal Medicine I, Klinikum Grosshadern, University of Munich, Germany.	Ther Apher 2001 Jun;5(3):182-5 Abstract quote This review summarizes the state of the art of apheresis in hemolytic uremic syndrome (HUS) and in thrombotic thrombocytopenic purpura (TTP). Both entities are characterized by thrombotic microangiopathy, hemolytic anemia, and thrombocytopenia. While HUS often presents with renal insufficiency, cerebral involvement is more common in TTP. Recently, in TTP, a primary or secondary lack of activity of a von Willebrand factor (vWF) degrading enzyme was made responsible for the presence of unusually large vWF multimers causing platelet aggregation and thrombus formation in the microvasculature. In contrast, in familial HUS, a factor H deficiency with uninhibited complement activation seems to play a role. Therapeutic plasma exchange (TPE) using fresh frozen plasma or cryosupernatant as the substitution fluid is indicated in acute TTP and atypical HUS without antecedent diarrhea. As a rule, it will show good effectiveness, especially in the former entity. HUS in pregnancy should be treated by instant delivery whereas postpartum HUS may resolve using protracted courses of TPE. In contrast, in thrombotic microangiopathy after bone marrow transplantation as well as in HUS due to cancer, mitomycin C, or after renal transplantation, TPE is of questionable value and indicated only as a last resort treatment.
TRANSPLANTATION
Combined kidney and liver transplantation for familial haemolytic uraemic syndrome. Remuzzi G, Ruggenenti P, Codazzi D, Noris M, Caprioli J, Locatelli G, Gridelli B. Ospedali Riuniti, Bergamo, Italy.	Lancet 2002 May 11;359(9318):1671-2 Abstract quote Recurrent haemolytic uraemic syndrome (HUS) is a genetic form of thrombotic microangiopathy that is mostly associated with low activity of complement factor H. The disorder usually develops in families, leads to end stage renal disease, and invariably recurs after kidney transplantation. We did a simultaneous kidney and liver transplantation in a 2-year-old child with HUS and a mutation in complement factor H to restore the defective factor H, with no recurrence of the disease. The operation was successful, and at discharge, the child had healthy kidney and liver function, with no sign of haemolysis.