Acute Renal Failure In Children Research Articles

Acute renal failure in children and infants

This review provides an overview of various topics related to acute renal failure and summarizes the results of recent advancements of particular significance in the care of children with acute renal failure. Over the past two decades, the treatment and prognosis of children with acute renal failure has notably shifted owing to advances in continuous treatment modalities, improvements in vascular access, and increased acknowledgment and understanding of the importance of optimizing nutritional support. After discussing the various causes of acute renal failure in children and infants, this review focuses on recent advancements in the management of acute renal failure, including acute dialysis modalities and continuous renal replacement therapy.

Active Site-Inactivated Recombinant Factor VIIa Blocks Shiga Toxin-Induced Upregulation of Tissue Factor Activity on Human Glomerular Endothelial Cells and Human Proximal Tubular Epithelial Cells.

Post-diarrheal hemolytic uremic syndrome (HUS), the leading cause of acute renal failure in children, is most often caused by Shiga toxin (Stx)-producing Escherichia coli infection. The most widely recognized tissue damage in HUS occurs within the kidney, most prominently with local thrombosis and platelet-fibrin accumulation, suggesting activation of the coagulation cascade. We have shown that human proximal tubular epithelial cells (HK-2 cells) exposed to Stx-1 augment their constitutive surface tissue factor (TF) activity by 3.2-fold, and that Stx-1 treatment following TNF-alpha exposure enhances TF activity by 2.7-fold on human glomerular endothelial cells (HGECs). We investigated the possibility of modulating this cellular response to Stx-1 by blocking the TF pathway with active site-inactivated recombinant factor VIIa (irFVIIa), which retains the ability to bind TF, but is enzymatically inactive, thereby inhibiting thrombin formation. Moreover, its action is limited to exposed, functional TF and does not significantly prolong the bleeding time in vivo. Monolayers of both HK-2 cells and TNF-alpha-activated HGECs were incubated at 37°C with Stx-1. Functional TF was determined chromogenically as the production rate of factor Xa. The use of 60 nM irFVIIa completely abrogated the enhanced activity of TF caused by 4 hours incubation with 10 pM Stx-1 of TNF-alpha-activated HGECs (N = 4; Figure 1). On HK-2 cells, irFVIIa (60 – 200 nM) also effectively reversed the observed TF upregulation after exposure to 1 nM Stx-1 for 22 hours as well as blocked the constitutive TF expression which is seen with this cell type (N = 3; Figure 2). The TF pathway may prove to be of major importance in the pathogenesis of HUS, and direct targeting of this pathway with irFVIIa might provide a novel therapeutic approach to this disease. [Display omitted] [Display omitted]

Shiga toxin binds to activated platelets

Hemolytic uremic syndrome (HUS) is associated with acute renal failure in children and can be caused by Shiga toxin (Stx)-producing Escherichia coli. Thrombocytopenia and formation of renal thrombi are characteristic of HUS, suggesting that platelet activation is involved in its pathogenesis. However, whether Shiga toxin directly activates platelets is controversial. The present study evaluates if potential platelet sensitization during isolation by different procedures influences platelet interaction with Shiga toxin. Platelets isolated from sodium citrate anticoagulated blood were exposed during washing to EDTA and higher g forces than platelets prepared from acid-citrate-dextrose (ACD) plasma. Platelet binding of Stx was significantly higher in EDTA-washed preparations relative to ACD-derived platelets. Binding of Stx was also increased with ACD-derived platelets when activated with thrombin (1 U mL-1) and exposure of the Gb3 Stx receptor was detected only on platelets subjected to EDTA, higher g forces or thrombin. EDTA-exposed platelets lost their normal discoid shape and were larger. P-selectin (CD62P) exposure was significantly increased in EDTA-washed preparations relative to ACD-derived platelets, suggesting platelet activation. Taken together, these results suggest that direct binding of Stx occurs only on 'activated' platelets rather than on resting platelets. The ability of Stx to interact with previously activated platelets may be an important element in understanding the pathogenesis of HUS.

ARF in children with minimal change nephrotic syndrome may be related to functional changes of the glomerular basal membrane

Background: Acute renal failure (ARF) is a rare complication in children with minimal change nephrotic syndrome (MCNS). Several etiologic factors (renal vein thrombosis, side effect of such drugs as nonsteroidal anti-inflammatory drugs, and infections) have been described, but often such conditions are lacking, and hemodynamic derangements or changes in glomerular permeability are suspected. Methods: We assessed the role of alterations in renal perfusion and glomerular permeability by measuring clearances of inulin and para-aminohippurate before and during intravenous administration of a 20% albumin solution in patients with MCNS and oliguric ARF (serum creatinine > 1 mg/dL [88 μmol/L], urine output < 0.5 mL/kg body weight/h). Results: Eleven patients aged 2.5 to 15 years with biopsy-proven MCNS were studied. Before albumin administration, all patients had a significantly decreased glomerular filtration rate (GFR), whereas most renal plasma flow (RPF) values were within the normal range. This resulted in a significantly decreased filtration fraction (FF; GFR/RPF × 100), which was extremely low (<7%) in 4 patients. There was a heterogeneous response to albumin administration. Albumin infusion tended to increase RPF, but changes did not reach statistical significance. Some patients showed an increase in glomerular filtration, whereas in others, it decreased. In 7 patients, FF remained unchanged or decreased even further. Conclusion: Our data suggest that, although in some patients decreased intravascular volume may contribute to reduced renal function, changes in glomerular permeability may have a major role in ARF occurring in uncomplicated MCNS.

Infection by Shiga toxin-producing Escherichia coli: an overview.

Shiga toxin-producing Escherichia coli (STEC), especially of serotype O157:H7, cause a zoonotic food or waterborne enteric illness that is often associated with large epidemic outbreaks as well as the hemolytic uremic syndrome (HUS), the leading cause of acute renal failure in children. After ingestion, STEC colonize enterocytes of the large bowel with a characteristic attaching and effacing pathology, which is mediated by components of a type III secretion apparatus encoded by the LEE pathogenicity island. Shiga toxins are translocated from the bowel to the circularoty system and transported by leukocytes to capillary endothelial cells in renal glomeruli and other organs. After binding to the receptor globotriaosylceramide on target cells, the toxin is internalized by receptor-mediated endocytosis and interacts with the subcellular machinery to inhibit protein synthesis. This leads to pathophysiological changes that result in HUS. Specific therapeutic or preventive strategies are presently not available. The recent sequencing of genomes of two epidemic E. coli O157 strains has revealed novel pathogenicity islands which will likely provide new insights into the virulence of these bacteria.

Decrease of thrombomodulin contributes to the procoagulant state of endothelium in hemolytic uremic syndrome.

The typical form of hemolytic uremic syndrome (D+HUS) is a thrombotic microangiopathy that causes acute renal failure in children. The etiology of this disease is a toxin called Shiga-like toxin (Stx), present in certain strains of gram-negative bacteria. Vascular endothelial cell (EC) injury appears to be central in the pathogenesis of D+HUS. Thrombomodulin (TM) is a glycoprotein present in EC with anti-thrombogenic properties. The objective of this study was to investigate the effects of Stx on the surface expression of TM in EC using an in vitro culture of human glomerular microvascular endothelial cells. We also evaluated other inflammatory mediators [tumor necrosis factor-alpha (TNF-alpha) and lipopolysaccharide], which are known to increase Stx receptor expression and are potentially involved in the pathogenesis of D+HUS. Stx2 induced a significant decrease of TM expression in this cell type after pre-incubation with TNF-alpha. This decrease could not be attributed to the inhibition of protein synthesis only, as cycloheximide, another inhibitor of protein synthesis, did not affect TM surface expression. These results suggest that the Stx2-induced decrease of TM expression in glomerular EC might contribute to the local procoagulant state present in D+HUS.

The medical significance of Shiga toxin-producing Escherichia coli infections. An overview.

Shiga toxin (Stx)-producing Escherichia coli (STEC), also referred to as Verocytotoxin-producing E. coli (VTEC) (), are causes of a major, potentially fatal, zoonotic food-borne illness whose clinical spectrum includes nonspecific diarrhea, hemorrhagic colitis, and the hemolytic uremic syndrome (HUS) (, , , , ). The occurrence of massive outbreaks of STEC infection, especially resulting from the most common serotype, O157:H7, and the risk of developing HUS, the leading cause of acute renal failure in children, make STEC infection a public health problem of serious concern (,,). Up to 40% of the patients with HUS develop long-term renal dysfunction and about 3–5% of patients die during the acute phase of the disease (, , , ). There is no specific treatment for HUS, and vaccines to prevent the disease are not yet available. The purpose of this overview is to highlight the public health impact, epidemiology, and clinicopathological features of STEC infection.

Acute renal failure in childhood.

The definition of acute renal failure is a sudden reduction in renal function of at least 50 percent and is characterised by rising serum levels of waste products such as urea and creatinine, by disturbed water and electrolyte metabolism and changes in the amount or composition of the urine. The clinical manifestations are extremely variable, there are very many causes and the outcome depends mainly on the underlying condition, which is either in the kidneys or in the body as a whole. This paper will discuss the pathophysiology of acute renal failure and the aetiology including prerenal, renal and postrenal causes. Clinical findings, diagnosis and treatment will be discussed and complications of this life-threatening condition highlighted. The final part of the paper deals with the prognosis of acute renal failure.

Antibiotics and Acute Renal Failure in Children with Cystic Fibrosis

Antibiotics and Acute Renal Failure in Children with Cystic Fibrosis

Shiga toxin-2 triggers endothelial leukocyte adhesion and transmigration via NF-κB dependent up-regulation of IL-8 and MCP-11: 1See Editorial by Siegler and Pysher, p. 1088.

Shiga toxin (Stx)-producing E. coli is a causative agent of the epidemic form of hemolytic uremic syndrome (HUS), the most common cause of acute renal failure in children. Endothelial injury and leukocyte activation are instrumental to the development of microangiopathic lesions. To obtain more insight into the mechanisms favoring endothelium-leukocyte interaction, we studied (1) the effect of Stx-2 on leukocyte adhesion and transmigration in human endothelial cells under flow; (2) the effect of Stx-2 on endothelial expression of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) and their functional role in the adhesive phenomena; and (3) the role of nuclear factor-kappaB (NF-kappaB) in endothelial chemokine expression. For adhesion experiments, human umbilical vein endothelial cells (HUVEC) and human glomerular endothelial cells (GEC) were incubated for 24 hours with Stx-2 (25 pmol/L), with or without anti-IL-8 or MCP-1 antibodies, and then exposed to leukocyte suspension under flow (1.5 dynes/cm2). IL-8 and MCP-1 expression was evaluated in Stx-2 treated endothelial cells (6 hours) by Northern blot. NF-kappaB activity was assessed by electrophoretic mobility shift assay. The role of NF-kappaB in Stx-induced chemokines was evaluated by transfecting HUVEC with an adenovirus coding for IkappaBalpha. Stx-2 significantly enhanced the number of leukocytes that adhered and then migrated across the endothelium. Stx-2 increased the expression of IL-8 and MCP-1, which was preceded by NF-kappaB activation. Blocking of endothelial IL-8 and MCP-1 with corresponding antibodies significantly inhibited Stx-induced leukocyte adhesion and migration either in HUVEC or GEC. Adenovirus-mediated gene transfer of IkappaBalpha down-regulated IL-8 and MCP-1 mRNA and also inhibited the adhesion and transmigration of leukocytes in Stx-treated HUVEC. Stx-2 via a transcriptional activation mechanism specifically mediated by NF-kappaB up-regulates endothelial MCP-1 and IL-8. Both chemokines are important modulators of leukocyte adhesion and transmigration under flow. These findings might be relevant to understand the nature of microvascular lesions in HUS and open future perspectives for better treatment of microvascular thrombosis.

Utilization of a Latex Agglutination Test for the Rapid Detection of Shigella in Stool Specimens of Children with the hemolytic Uremic Syndrome

Background: The hemolytic uremic syndrome (HUS) is one of the important causes of acute renal failure in childhood. It is classified into diarrhea-associated and atypical cases. Verotoxin-associated HUS is the most common type of the disease. It is characterized by the sudden onset of hemolytic anemia with fragmented erythrocytes, thrombocytopenia, and acute renal failure after a prodromal illness of acute gastroenteritis usually with bloody diarrhea. In addition to specific strains of E. Coli, Shigella dysentriae type 1 can be an important cause of HUS. Cases with Shigella dysentriae have ahigher mortality rate, and a greater incidence of complications and extra-renal manifestations compared with patients who have HUS related to E. Coli. Therefore, it would be important to have a rapid way to detect Shigella associated HUS, in order to anticipate its complications, and allow the administration of aggressive managements to such patients. Conventional stool cultures are labour-demanding and time-consuming, and therefore may not be the ideal method for the detection of certain stool pathogens in acute situation like the hemolytic uremic syndrome. A rapid, cost-effective and reliable method for the detection and identification of stool pathogens in stool specimens from these patients would be of great value. Objectives: The aim of this work is to evaluate the utilization of a rapid latex agglutination test in comparison to conventional stool culture to determine the incidence of Shigella dysentriae among children with the HUS in Egyptian children, and to determine whether this test could be used as an alternative to conventional stool culture in this situation. Methods: In this study, a latex agglutination test (Bactigen Salmonella/Shigellalatex agglutination slide test; Wampole Laboratories, Cranbury, NJ) was evaluated as a test for the detection of Shigella antigens in Gram Negative Broth for the early and rapid detection of Shigella dysentriae infection in infants and children presenting with evidence of the hemolytic uremic syndrome. Results: Utilization of conventional stool culture revealed that 3 of 7 cases of the HUS were positive for Shigella dysentriae, an incidenceof 17%. Utilization of the BSST latex agglutination test for Shigella antigen shows that 5 of 17 cases of the HUS were positive for Shigella dysentriae (29.5%). Also, all 3 cases in which stool culture was positive for Shigella dysentriae were also positive by the BSST test, with no false negatives (sensitivity 100%, positive predictive value 80%). However, of the 14 cases of HUS who were negative for Shigella by culture, two cases were positive for Shigella by the BSST latex agglutination test (specificity 85%, negative predictive value 100%). Conclusions: The BSST latex agglutination test is a useful method for the rapid detection of Shigella antigens in stool specimens from infants and children with the HUS. Due to its rapidity, it can provide a quick answer and allow the anticipation if the need for more aggressive managements for cases of HUS associated with Shigella gastroenteritis. Its sensitivity appears to be excellent. While its specificity appears to be low, with a high incidence of false positive results. However, in such an acute situation, it is much more important not to miss a positive case than to over-diagnosis a case with Shigellosis. Also, conventional stool culture can correctly identify the true pathogen in false positive cases.

Phenotype markers and function of neutrophils in children with hemolytic uremic syndrome.

The hemolytic uremic syndrome (HUS) is the most-common cause of acute renal failure in children. Several researchers have reported the presence of neutrophil (PMN) activating cytokines, such as interleukin-8 and tumor necrosis factor-alpha, in the sera of HUS patients. Moreover, PMN-derived products, such as elastase, were increased. These observations have lead to the hypothesis that activated PMN could act as mediators of endothelial damage. The objective of this investigation was to directly evaluate the activation status of peripheral PMN from children with HUS. For this purpose, 12 children with typical HUS were bled during the acute period, before dialysis and/or transfusion, and 8 of them were also bled after 1 month follow-up. Additionally, blood samples from healthy control children admitted for routine surgical procedures, chronic uremic children, and neutrophilic children with acute infections not related to HUS were collected and processed in an identical manner. The function and membrane activation markers of PMN from these groups were evaluated. We found that during the acute period of HUS, PMN had reduced expression of FcgammaRIII (CD16) and CD11b, were degranulated, and exhibited an impaired antibody-dependent cellular cytotoxicity. These parameters returned to normal after clinical recuperation. We conclude that PMN activation in HUS patients is a very early and transient event, and upon hospitalization before dialysis PMN show a phenotype and functional pattern of partial deactivation.

Acute renal failure.

Acute renal failure is characterized by an increase in the blood concentration of creatinine and nitrogenous waste products and by the inability of the kidney to appropriately regulate fluid and electrolyte homeostasis. There are many different causes of acute renal failure in children, including prerenal disease, intrinsic renal failure, which includes ischemic hypoxic insults, and obstructive uropathy. This review will focus on hypoxic/ischemic acute renal failure, the most common causes of hospital acquired acute renal failure in children. This review will briefly discuss the epidemiology and incidence of acute renal failure in pediatric patients and review new insights into the pathogenesis of acute renal failure. including hemodynamic alterations induced by alterations in nitric oxide and endothelin metabolism, the role of the inflammatory response, and alteration in polarity in the acute renal failure. The therapy of acute renal failure has changed substantially during the past few years. Controlled trials (in adults) to test the efficacy of "renal dose" dopamine have shown that it is ineffective, and hemofiltration has become increasingly popular as a choice of therapy for acute renal failure.

Kidney failure in infants and children.

1. James C. M. Chan, MD*† 2. Debra M. Williams, MD* 3. Karl S. Roth, MD*† 1. *Department of Pediatrics, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA 2. †Department of Biochemistry, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, VA After completing this article, readers should be able to: 1. Recognize and delineate the causes of acute renal failure. 2. Formulate emergency management of fluid electrolyte disorders in acute renal failure. 3. Characterize the incidence, causes, and costs of chronic renal failure in children. 4. Explain the pathogenesis and treatment of complications of chronic renal failure. 5. Delineate a plan to help the family with the outcome of renal failure. The evaluation of kidney failure is challenging, despite many advances in diagnosis and treatment over the past decade. To provide pediatricians with an informed choice, this article reviews both acute and chronic renal failure, their multiple causes, the principles of treatment, and both short- and long-term outcomes. Acute renal failure (ARF) is characterized by the abrupt failure of the kidneys to regulate water and electrolyte homeostasis. ARFs in childhood due to hemolytic-uremic syndrome, postinfectious acute glomerulonephritis, or dehydration are reversible, but a small percentage may progress to chronic renal failure (CRF). CRF is the result of slowly progressive kidney diseases and seldom is fully reversible. This condition in childhood is associated with obstructive uropathy, congenital aplastic/hypoplastic/dysplastic kidneys, and other causes. In CRF, almost every system in the body eventually becomes compromised. ### Incidence and Causes ARF is encountered in 3% to 10% of all admissions to neonatal intensive care units. In our experience with a regional pediatric nephrology program serving a catchment area of 1.5 million general population, 6.4% of 3,154 children referred to the program from community physicians suffered from ARF. However, precise figures on the true incidence of ARF in childhood are surprisingly sparse. ARF is a life-threatening, abrupt reduction of urinary output to less than 300 mL/m2 per day that is precipitated by prolonged renal ischemia in most cases. Occasionally, it may present with a high urinary output but mounting serum urea nitrogen and creatinine …

Depletion of liver and splenic macrophages reduces the lethality of Shiga toxin-2 in a mouse model.

The haemolytic uraemic syndrome (HUS) is a clinical syndrome consisting of haemolytic anaemia, thrombocytopenia, and acute renal insufficiency. HUS is the most frequent cause of acute renal failure in childhood. It has been previously suggested that the presence of Shiga toxin (Stx) is necessary but not sufficient for HUS development, and cytokines such as tumour necrosis factor-alpha (TNF-alpha) and IL-1beta appear to be necessary to develop the syndrome. Since the mononuclear phagocytic system (MPS) is the major source of these cytokines, macrophages might be one of the relevant targets for Stx action in the pathophysiology of HUS. In this study our objective was to examine the role of the hepatic and splenic macrophages in a mouse model of HUS induced by injection of Shiga toxin type-2 (Stx2) or Stx2 plus lipopolysaccharide (LPS). For this purpose, depletion of mice macrophages by liposome-encapsulated clodronate (lip-clod), followed by injection of STx2 or Stx2 plus LPS, was assayed. In this study we show that depletion of hepatic and splenic macrophages by clodronate treatment induces a survival of 50% in animals treated with Stx2 alone or in presence of LPS. This maximal effect was observed when lip-clod was injected 48-72 h before Stx2 injection. Biochemical and histological parameters show characteristics of the lesion produced by Stx2, discarding non-specific damage due to LPS or lip-clod. In addition, we determined that the toxic action of Stx2 is similar in BALB/c and N:NIH nude mice, indicating the T cell compartment is not involved in the Stx2 toxicity. Briefly, we demonstrate that macrophages play a central role in the pathophysiology of HUS, and that the systemic production of cytokines by liver and/or spleen is for Stx2 to manifest its full cytotoxic effect. In addition, the toxicity of Stx2 alone, or in presence of LPS, is independent of the T cell compartment.

Rhabdomyolysis and acute renal failure in children.

Acute renal failure (ARF) is an important complication of rhabdomyolysis. However, the contributing factors to the development of ARF in children with rhabdomyolysis remain obscure. The aim of this study was to clarify the factors contributing to the development of ARF in children with rhabdomyolysis. This is a retrospective review of the clinical characteristics, laboratory data, pediatric risk of mortality (PRISM) scores, the occurrence of systemic inflammatory response syndrome (SIRS) criteria, and the number of dysfunctional organs in 18 children with rhabdomyolysis seen in our hospital between 1991 and 2000. The patients were divided into an ARF group (n=9) and a non-ARF group (n=9). All patients with ARF had more than two dysfunctional organs. The incidence of dehydration, serum concentrations of myoglobin, creatinine kinase, aspartate aminotransferase, and lactate dehydrogenase, PRISM scores, and the numbers of SIRS criteria and dysfunctional organs were higher in the ARF group than the non-ARF group. The blood pH and base excess, and urinary pH were lower in the ARF group than in the non-ARF group. These results suggest that ARF is more likely to develop in the presence of dehydration, metabolic acidosis, or severe muscle damage, or with multiple organ failure in children with acute rhabdomyolysis.

Secondary sclerosing cholangitis and portal hypertension after O157 enterocolitis: Extremely rare complications of hemolytic uremic syndrome

The authors experienced an extremely rare case of secondary sclerosing cholangitis and portal hypertension developed as late complications of hemolytic uremic syndrome (HUS) owing to Escherichia coli O157:H7 in a 2-year-old boy. HUS after E coli O157 infection is the most frequent cause of acute renal failure in childhood and occasionally is accompanied by extrarenal complications such as encephalopathy, cardiomyopathy, ischemic colitis, and pancreatitis. Rarely, late colonic stenosis may develop secondary to the ischemic damage. Sclerosing cholangitis and subsequent cirrhosis with portal hypertension are very uncommon as late complications of HUS. To our knowledge, such a case has not been previously reported in the literature. J Pediatr Surg 36:1838-1840. Copyright © 2001 by W.B. Saunders Company.

Hemolytic-Uremic Syndrome

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).

Vero cytotoxin binding to polymorphonuclear leukocytes among households with children with hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS), the leading cause of acute renal failure in childhood, can be caused by different serotypes of vero cytotoxin (VT; i.e., Shiga toxin)-producing Escherichia coli (VTEC). Recently, VT was shown to bind to polymorphonuclear leukocytes (PMNL) in the systemic circulation of patients with HUS. This study investigated whether VT bound to PMNL could be detected in persons in households with patients with HUS. Serum antibodies against E. coli O157 and, when available, fecal samples from patients with HUS and household members were studied for the presence of VTEC infection. The circulating PMNL of 82% of the household members were positive for VT, whereas stool and/or serum examination showed only 21% positivity. Thus, current methods underestimate the number of infected persons in households with patients with HUS.

Detection of verocytotoxin bound to circulating polymorphonuclear leukocytes of patients with hemolytic uremic syndrome.

The epidemic form of hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in children and is characterized by a prodromal phase of sometimes bloody diarrhea. The role of verocytotoxin (VT)-producing Escherichia coli has been strongly implicated. Although antibodies against VT have been detected in the serum of patients with HUS, VT itself has never been detected in circulating blood. In this study, VT-2 was detected in the systemic circulation in 9 of 10 patients with the epidemic form of HUS. In those cases, VT-2 was bound exclusively to polymorphonuclear leukocytes (PMN). The detection of VT-2 bound to PMN was associated with the presence of diarrhea at the time the blood samples were obtained. The one patient for whom VT was not detected presented with atypical HUS. For 5 of the 10 patients with HUS who were studied, the time course of VT binding was analyzed; binding decreased in four patients. The finding of VT bound to PMN in the systemic circulation of patients with HUS is important for a clearer understanding of the pathogenesis of HUS and suggests new approaches for treatment in the future.