Hemolytic-uremic syndrome

Hemolytic-Uremic

Syndrome

Wm. Lane M. Robson, M.D., F.R.C.P.(C) Alexander K.C. Leung, M.B.B.S., F.R.C.P.(C) Bernard S. Kaplan, M.B., B.Ch. Introduction Hemolytic-uremic syndrome (HUS) is one of the most common causes of acute renal failure in infancy and childhood. The spectrum of the syndrome varies from subclinical illness to fulminating lifethreatening disease. Our understanding of the pathogenesis of HUS has increased in the last decade and although this improved understanding has not led to any breakthroughs in treatment, there are therapeutic and preventative possibilities for the future. This article reviews the classification, epidemiology, etiology, pathogenesis, clinical presentation, treatment, and prognosis of patients with HUS.

Historical Aspects In 1955 Gasser and colleagues described five children with acute hemolytic anemia, thrombocytopenia, and renal failure who died during the acute stage of the illness. * Brain and associates attributed the erythrocyte abnormalities to damage of the vascular endothelium and were the first to use the term “microangiopathic hemolytic anemia” to describe this condition.’ The syndrome, now known as HUS, consists of the triad of a microangiopathic hemolytic anemia (with fragmented red blood cells), thromboWm. Lane M. Robson, M.D., F.R.C.P.(C), is Head of the Division of Pediatric Nephrology, and Alexander K. C. Leung, M.B.B.S., F.R.C.P.(C), is Clinical Associate Professor, in the Department of Pediatrics, Faculty of Medicine, The University of Calgary and the Alberta Children’s Hospital, Calgary, Alberta, Canada. Bernard S. Kaplan, M.B., B.Ch., is Professor and Head of the Division of Pediatric Nephrology at the University of Pennsylvania and the Children’s Hospital of Philadelphia, Philadelphia.

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cytopenia, and acute renal injury. Since Gasser and colleagues first described HUS, thousands of cases have been reported.3

Classification HUS can be classified into diarrhea-associated (D+) HUS, and non-diarrhea-associated (D-) HUS. DHUS may be familia14-6 or sporadic. In the past, most reports have grouped D+ HUS and D- HUS together. Because the causes, clinical courses, and prognoses of these two types are different, cases should be defined and reported separately. 7, ’

Epidemiology Originally, HUS was considered to be endemic to specific geographic areas such as Argentina,‘-” the Netherlands,” South Africa,i3 and California.7 HUS is now recognized worldwide. Table 1 shows the reported incidence of HUS in various geographic areas.14-18 Blacks are less frequently affected than whites. l9 There is evidence that the incidence of HUS is increasing at a rate greater than would be expected by improved awareness alone. Tan: and Hickman calculated that from 1971 to 1978, a child residing in King County in Washington had a 1 in 5,747 chance of developing HUS by age 15 years.14 Their incidence data from 1979 to 1982 suggested that the risk of developing HUS was at least 1 in 2,374.14 The mean annual incidence in Minnesota increased from 0.5/100,000 in 1979 to 2/100,000 in 1988.18 Experience

TABLE 1 Incidence of Hemolytic-Uremic Syndrome in Different Geographic Areas Aurthors Tarr and Hickman14 Rogers et all5 Rowe et a1.16 Abu-Arafeh et a1.17 Martin et al.”

Location Washington, U.S.A. Oregon, U.S.A. Canada Northeast Scotland Minnesota, U.S.A.

in southern Alberta, Canada, confirms an increase in the incidence of HUS.*’ Similar findings have been noted by Milford and colleagues in the United Kingdom.*i D+ HUS is more frequent than D- HUS.4 In a study based on 86 children with HUS assessed in Toronto, Ontario, Canada, from 1980 to 1986, 91% of the children had D+ HUS and 9% had D- HUS.*’ The age of onset of D+ HUS ranges from the neonatal period to adulthood, but HUS tends to occur predominantly between the ages of 6 months and 4 years. I9 In contrast, D- HUS does not have an age predilection.” The sex distribution in most studies is equal, although a slight female reponderance has been noted in some studies.‘6, ’ r ’ ‘* In the Northern Hemisphere there is a definite seasonal predilection for D+ HUS, with the majority of patients presenting in the warmer spring, summer, and early fall months.16, 23 In D- HUS, there is no seasonal variation in incidence.23 D+ HUS has a predilection for children from families with a higher socioeconomic status.‘, 16, 24 We reported an increased incidence of D+ HUS in children whose father was either a physician or a lawyer.24 Of 43 children with D+ HUS, 6 (14%) came from a family with a father belonging to one of these two professions.24 Simultaneous occurrence of HUS in related and unrelated adopted siblings has been reported.5, 25 Epidemics of D+ HUS have occurred in day care centers and institutions?*’

Etiology In North America, HUS is most often associated with infection by verocytotoxin-producing Escherichiu coli (VTEC). 29 There are at least 24 serogroups of VTEC associated with hemorrhagic colitis or D-t HUS.29 The most common serotype is E. coli 0157:H7, although serotypes such as 026, 0111, 0113, 0121, and 0145 are also detected.29 Other bacteria that have been reported in association with D+ HUS include Shigella dysenferiue type

Years of Study 1971-1980 1979-1982 1986- 1988 1978-1989 1988

Incidence per 100,000 Children 1.16 0.97

1.44 1.25 2.00

1,30 Salmonella fyphimurium and senftenberg,3* Cumpylobucfer jejuni,32 Yersiniu enferocolificu,33 and Aeromonus hydrophilu. 34, 35 The frequency of identification of each pathogen varies in different geographic locations. VTEC is transmitted primarily by food29 and is found in 1.5% to 3.7% of fresh samples of beef, pork, poultry, and lamb obtained from retail food outlets in the United States and Canada.36 E. coli 0157:H7 is an inhabitant of the intestinal reservoir of beef cattle.37 The bacteria contaminate the surface of beef during the slaughtering process. The organism is usually killed in steak or roast cuts of beef if the surface is well cooked. Undercooked beef hamburger appears to be a common source of VTEC. Since the surface of hamburger is inside as well as outside of the meat,*’ if hamburger is not thoroughly cooked, the VTEC on the inside surface may survive. The first report of the association of E. coli 0157:H7 and hemorrhagic colitis in humans involved the patrons of a fast-food restaurant and the ingestion of contaminated beef hamburger patties.38 Numerous reports have confirmed the association of epidemic and sporadic hemorrhagic colitis and D+ HUS due to VTEC and the ingestion of hamburger.27, 29, 39, a VTEC has been found in milk filters from dairy farms and has also been traced to unpasteurized milk, cheese, and well water.29 Person-to-person spread is an important mode of transmission, particularly in settings such as da care centers,*’ institutions for the handicapped, 27 and nursing homes. 26, 39 Epidemiologic studies have identified a secondary person-to-person spread of hemorrhagic colitis due to E. co/i 0157:H7 subsequent to an initial attack due to a contaminated food source.26’ *’ A study by the Canadian Pediatric Kidney Disease Registry found that person-to-person spread is an im ortant source of VTEC in patients with D+ HUS.’ fF Familial D- HUS may be inherited in an autosoma1 dominant or recessive pattern.5 Sporadic D- HUS may be associated with medications such as oral contraceptives,41 cyclosporine,42 mitomycin C, 43, 44 5-fluorouracil,44 deoxycoformy-

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cin,45 cisplatin, 46 bleomycin, 46 vincristine,% and quinine47; nongastrointestinal infections due to chickenpox, 48 Coxsackie B virus, 49 echovirus, 5o influenza viru~,~* Epstein-Barr viru~,~~ Tacaribe-group viru~,~~ i1 arbovirus,‘2 Microf~tobiotes,~~ and Streptococcus pneumoniue;54 and miscellaneous conditions including Kawasaki disease,55 acute rhabdomyolysis,56 acute bromate poisoning,57 pregnan?l,58 and renal and bone marrow transplantation. 59-6 The evidence for an association between each of these and HUS varies from soft and circumstantial to convincing.

Pathogenesis The abnormalities in D+ and D- HUS are believed to develop as a consequence of damage to endothelial cells primarily in the kidneys, but also in the other organ systems. 63-66 Endothelial injury leads to a loss of antithrombotic properties of the blood vessel wall with subsequent intravascular platelet activation.67 A possible sequence of events leading to renal damage in D+ HUS is shown in Figure 1. The major steps in this schema require initiation of endothelial damage, Shiga-like toxin (SLT), activation of white blood cells (WBCs), and local coagulation in small arterioles. Bacteria associated with D+ HUS elaborate both SLT and lipopolysaccharide (LPS), an endotoxin. SLT and LPS are absorbed from the gastrointestinal tract and cause damage to the endothelial cells in the kidney and other organs, directly or indirectly, and by the activation of neutrophils. Cytokines such as interleukin1 and tumor necrosis factor-a may also be involved.63, 68 Activated neutrophils damage endotheShiga-like

E coli

toxin from or Shiaella dvsenteriae . \

type

I

Shrn;olii;z;;e

cell

damage

cell

activation

piatele~raction I platelet

thrombi

acute

t

in giomerular I re&l

t

injury

FIGURE 1 Possible sequence diarrhea-associated

of events leading hemolytic-uremic

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lial cells by intracellular enzymes63, 68 and/or oxygen radicals.69 Once endothelial cells are damaged, a platelet-endothelial cell interaction occurs.65 Vasoactive and platelet-aggregating substances are released from damaged endothelial cells and result in the formation of platelet thrombi in renal microvessels and subsequent acute renal injury.65 Shiga-like Toxin SLT, a cytotoxin elaborated by specific strains of E. coli, causes endothelial damage.29 Karmali and colleagues found evidence of infection with SLT in 73% of Canadian children with D-t HUS.70 S. dysenteriue type 1 is associated with D+ HUS and also elaborates a cytotoxin (Shiga toxin).29 VTEC-associated HUS occurs in the Western Hemisphere, whereas S. dysenferiue type l-associated HUS is common in Southeast Asia.30, 7* Shiga toxin is a 71-kDa multisubunit complex comprised of a single 32-kDa “Asubunit” and five 7.7-kDa “B-subunits.“29* 65 SLT is almost identical to Shiga toxin. Two SLTs elaborated by VTEC have been identified: Shiga-like toxin 1 (SLTl) and Shiga-like toxin 2 (SLT2).29 Although the SLTs are immunologically distinct, the taxonomic diversion may have little biologic relevance. The SLTs may have identical cell receptors, mechanisms of action, and pathogenetic significance. 72 Each strain of VTEC may produce one SLT or more.2*, 73 In this communication the cytotoxins are collectively referred to as SLT. The “B-subunit” of SLT is responsible for binding of the cytotoxin to gl colipid receptors on the surfaces of sensitive cells. ‘, 65, 74 The glycolipid receptor contains the terminal disaccharide galactose (lo+@) galactose, which binds to these cells.29, 66 Globotriosyl ceramide (GB,) is a receptor for SLT.29, 66 Binding is followed by internalization of the “A-subunit,” which inhibits protein synthesis by inactivating 60 S .ribosomal subunits through selective structural modification of 28 S ribosomal RNA.@j This may lead to endothelial cell damage or death.” SLT has not been detected in sera, possibly because of its very short half-life in serum.29’ 75 It has been suggested that SLT causes mucosal erosions in the gastrointestinal tract and that the erosions ma allow the entry of endotoxins into the circulation. 2 There may be a synergistic enhancement of the effect of SLT bg LPS, possibly by increasing mucosal permeability. VTEC possesses a fimbrial anti en that allows adherence to intestinal mucosal cells. F2 Rabbits injected intravenously with purified SLT developed paralysis of the limbs, oliguria, and nonbloody diarrhea prior to death.78 The most pronounced histopathologic findings were in the intestine and the central nervous system (CNS). The en-

dothelial cells in the spinal cord were swollen.78 Characteristic CNS findings included edema, hemorrhage, and infarction secondary to thrombotic microangiopathy. The lack of renal pathology in the rabbit may be due to the absence of GBa in rabbit kidneys. In contrast, GB3 is present in abundance in human kidneys. 79

was suggested that these interactions may represent a prelude to phagocytosis or schistocyte formation.gO Rabbits develop pathologic lesions similar to HUS subsequent to injection with LPS extracted from S. dysenteriue type 1, but rabbits rendered leukopenic by prior busulphan treatment are protected against LPS-induced renal cortical necrosis.”

White Blood Cells Several lines of evidence implicate a role for WBCs in the pathogenesis of HUS. WBC counts are elevated in the blood80, *I and urine2’ of patients with D+ HUS. WBCs have also been noted in the glomeruli and interstitium of kidney tissue obtained by biopsy or autopsy from patients with HUS.82-85 Fecal WBC counts are not usually elevated.66 Neutrophils are capable of causing endothelial injury by a number of mechanisms. The intracytoplasmic granules of neutrophils contain catabolic enzymes, including elastase, which may account for up to 60% of the endothelial injury caused by neutrophilss6 Serum elastase and its inhibitor, cY,-antitrypsin, are markedly elevated in patients with HUSs7 It has been shown that elastase can cleave von Willebrand factor (vWF) in vitro.87 A single polymorphonuclear leukocyte per endothelial cell supplies enough elastase to inhibit the production of thrombin-induced $r;T& JPpg15~yin,e ‘i: [PGI,]) production. mediator of endothelial cell detachment, possibly by the degradation of fibronectin, which is an important cell marker of damage to the endothelium.87 Forsyth and colleagues studied neutrophil-induced endothelial injury as assessed morphologically by the degradation of endothelial cell fibronectin, and found that the proportion of neutrophils adhering to endothelium in culture was twice as high for neutrophils from patients with HUS compared with those from controls. 68 In an attemp t to inhibit neutrophil adhesion and subsequent endothelial damage, hyperadhesive neutrophils from patients with HUS were incubated with an antibody directed against the common B-chain of the leukocyte integrin molecule.68 The antibody prevented the endothelial damage in 4 of the 10 subjects studied.68 Changes in neutrophil function were studied in a rabbit model of the modified generalized Shwartzman reaction which resembles HUS. 89 Enzyme release by neutrophils, impairment of chemotaxis and aggregation, and increased procoa lant content in neutrophils were demonstrated.’ $u Activated neutrophils also generate reactive oxygen radicals that are capable of causing oxidative damage to cell membranes4, 69 Tactile interactions were noted between damaged red blood cells and leukocyte cell processes, and it

Abnormalities in Coagulation Because glomerular deposits of fibrin can be demonstrated in most patients with HUS, initial research into the pathogenesis of HUS focused on abnormalities in the coagulation and fibrinolytic process. Persistence of fibrin within glomeruli may be due to reduced fibrinolytic activity. 63 Hemolysis occurs as red blood cells pass through damaged renal arterioles and fibrin thrombi form on damaged endothelial surfaces.2 Hemolysis may also occur as a direct result of lipid peroxidation. Peroxidative damage, as evidenced by depressed red blood cell phosphatidylethanolamine and plasma tocopherol levels,92 and a disturbance in the metabolism of vitamin E93 have been observed in patients with HUS. Thrombocytopenia may result from platelet destruction, increased consumption, sequestration in the liver and spleen, intrarenal aggregation, or a combination of these factors.63 The remaining platelets in the circulation appear to be “exhausted,” which may result from direct toxic injury to the platelets or involvement in the local coagulation process.94 These platelets circulate in a degranulated form, depleted of nucleotide and granule contents, and from a functional perspective demonstrate a pattern characteristic of impaired aggregation.94 Platelets have a receptor for SLT and may be specifically affected by these cytotoxins.4 Much research regarding the roles of PGI,, an anti-platelet-aggregating agent, thromboxane A, (TXA,), a platelet-aggregating agent, and vWF multimers, platelet-aggregating agents, has led to the speculation that these factors are implicated in the pathogenesis of the thrombocytopenia.63 PGI, and vWF multimers are produced in the vascular endothelium. TXA2 is produced in platelets and in the renal cortex. 67 At least three abnormalities of PG12 metabolism in HUS, including a deficiency of a plasma factor required for PGI, production, inhibition of PGI, production, and increased degradation of PGI,, have been reported. 64, 95 Intravascular platelet activation in D+ HUS may be due to defective PGI, production, whereas abnormal PGI, synthesis may be the cause in D- HUS. 96 The plasma concentrations of 6-keto-prostaglandin Fla, a stable metabolite of PGI,, are low during the acute phase of HUS, but not durCurrent Problems

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ing early convalescence and after clinical recovery.97 The initial decrease of PG12 and its metabolites may be due to either decreased rduction secondary to damage to the endothelium or increased consumption.97 The subsequent increase in PGI, and its metabolites may be due to recovery of the vascular endothelium. TXA, is increased during the acute phase of HUS.98 This enhanced biosynthesis is consistent with increased platelet activation.98 Administration of a selective TXA, synthetase inhibitor prevented the fall in renal blood flow and significantly preserved the glomerular filtration rate (GFR) in a rat model of endotoxin-induced acute renal failure.76 Unusually large vWF multimers have a severalfold greater ability in vitro to aggregate platelets, compared to the vWF multimers in the plasma of normal children and adults. A degrading factor in normal plasma has the ability to convert unusually large vWF multimers into the somewhat smaller vWF multimers found in the normal circulation.99 It is possible that this degrading factor is not functioning in patients with HUS. Miscellaneous S. pneumoniue elaborates neuraminidase, which has the capability to damage endothelial cells. Circulating neuraminidase removes N-acetylneuraminic acid from cell-surface glycoproteins and exposes the normally hidden T antigen (Thomsen-Friedenreich antigen), which is present on erythrocytes, platelets, and glomeruli . 53Once exposed, this antigen can react with the anti-T IgM antibody present in most human plasma and can produce the features of HUS.53, 65 Clinical Manifestations The mean incubation period of VTEC-associated hemorrhagic colitis is estimated to be 3 to 4 days (range, 3- 12 days).37, 39 Typically, a patient with hemorrhagic colitis due to VTEC presents with abdominal cramps, bloody diarrhea, tenesmus, and vomiting. Fever is present in approximately 5% to 20% of individuals.38, 39 An uncomplicated course evolves over an average of approximately 8 days. 37, 40 The duration of diarrhea in children with hemorrhap colitis is significantly longer than that of adults. Approximately 10% of children with hemorrhagic colitis due to VTEC will go on to develop D-t HUS.29 During episo des of epidemic hemorrhagic colitis, up to 40% of patients may develop D+ HUS,27 but the reason for this is not understood. It is speculated that immunologic factors or the quantity of the bacterial inoculum may play a role.29

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D+ HUS develops during or after an episode of diarrhea. Conversely, D- HUS does not follow a prodromal illness or may follow a respiratory illness. 74 In patients with D+ HUS, the onset may occasionally follow a trend to improvement in the diarrhea. Often the parents can date the onset of the D+ HUS to the day that their child appeared “sicker” or vomiting recurred. 2o The most common presenting symptoms and signs of HUS are pallor, a decrease in urine output, peripheral edema, and macroscopic hematuria. The child may appear irritable and abdominal tenderness may be present. Peripheral edema is more common in patients who are treated with parenteral fluids during the preceding episode of diarrhea before recognition of onset of oliguria. Hypertension occurs during the acute stage in approximately 35% to 50% of patients. Hepatosplenomegaly may be present.isa An incomplete form of D+ HUS may also occur. We assessed a child with transient hematuria, pyuria, and proteinuria in association with SLTassociated hemorrhagic colitis. Hemolytic anemia, thrombocytopenia, and acute renal failure were not present. Another child presented with hemolytic anemia and thrombocytopenia but without evidence of acute renal failure, and a third child developed hemolytic anemia, thrombocytopenia, and pancreatitis but without acute renal failure in the context of VTEC-associated hemorrhagic colitis.

Complications Renal System Acute renal failure is the most important complication. The duration of oliguria and anuria is variable but is usually less than a week.“’ The longest reported period of anuria was 75 days.lo2 Renal cortical necrosis may develop. Renal cortical calcification after prolonged anuria has also been described.io3 Long-term sequelae include chronic renal failure, reduced GFR, hypertension, and proteinuria.9-‘1 Hema tologic Sys tern Disseminated intravascular coagulopathy (DIC) has developed in patients with HUS, especially those associated with infection due to S. dysenteriue type 1104 or S. pneumoniae. Idiopathic thrombocytopenic purpura (Ill’) may occur several weeks to a year after recovery from HUS. lo5 The significance of the ITP is not known and may be coincidental. Central Nervous System The most common signs of CNS involvement are a decreased level of consciousness and seizures. Other

manifestations include irritability, nystagmus, pupillary abnormalities, ataxia, hypotonia, hemiparesis, hemiplegia, increased deep tendon reflexes, decerebrate or dystonic posturing, hallucination, and cortical blindness. Major neurologic complications are detected in approximately 40% to 50% of patients.“, lo6 CNS complications may be due to severe hypertension, electrolyte disturbances, or cerebral microthrombi.‘078 loa Computed tomographic (CT) scans of the brain may show diffuse cerebral edema, infarctions, thrombosis, or hemorrhage.lo7 CNS complications occur more frequerrr iraswith severe hyponatremia. ’ lo9 111 sociation Eighty-four percent of patients with seizures had hyponatremia compared to only 50% of those without seizures.“’ Convulsions occurred within 24 hours after detection of the lowest serum sodium level in 35 of the 55 children who presented with seizures.“’ Gastrointestinal System Gastrointestinal complications are common and include pancreatitis, rectal prolapse, intestinal stricture, intestinal perforation, intussusception,‘f2 se mental colonic gangrene,1’3 and hepatic damage.’ -7* The most characteristic abnormalities noted on radiographic and endoscopic studies of the gastrointestinal tract in patients with D+ HUS are edema, inflammation, and hemorrhage, predominantly in the ascending and proximal transverse colon.‘15 Of 29 children with D+ HUS, 19 (66%) had elevated serum levels of amylase and lipase and 6 (21%) had a marked elevation of serum ligase with additional evidence of acute pancreatitis.‘r Endocrine System Hyperglycemia is common in children with HUS who are on peritoneal dialysis. The hyperglycemia may be due to an excess glucose load from the peritoneal dialysate in the presence of a relative or absolute insulin deficiency due to pancreatic damage secondary to the HUS process. We reported on four patients with hyperglycemia associated with D+ HUS and reviewed the literature, finding a total of 13 children with this complication.“7 Hyperglycemia develops more frequently in children with severe HUS and in children with D+ HUS who are female, are anuric, or have a high WBC count.l17 Cardiovascular System Hypertension is more common in patients with evidence of extracellular fluid volume expansion. Some hypertensive children have high levels of plasma renin activity. 11* Myocardial involvement may include cardiomyopathy, cardiac aneurysm, or myocarditis.* Conges-

tive heart failure may result from myocardial involvement, volume expansion in the context of acute renal failure, and coexisting anemia. Integumentary System Petechiae and purpura are uncommon notwithstanding the thrombocytopenia. Ulcers of the buccal mucosa and gums and dry, cracked, easily bleeding lips with fissures have been described.*” We noted vesiculated lesions on the lips of five patients with D+ HUS.lzO Scrapings from lesions in two of the children revealed herpesvirus hominis by electron microscopy. rzo The herpetic lesions may have been triggered by the stress of the HUS. Muscular System Rhabdomyolysis has been reported with D+ HUS.‘*r

in association

Laboratory Findings A moderate to severe anemia is invariably present.63 The peripheral smear typically shows schistocytes, burr cells, helmet cells, spherocytes, and other red blood cell fragments (Fig 2). The schistocyte is characteristic of the microangiopathic hemolytic process. The degree of morphologic change of red blood cells correlates with the degree of anemia. The hemolytic anemia is associated with an increase in the serum bilirubin concentration, a decrease in serum haptoglobin, and an increase in the reticulocyte count.63 The direct and indirect Coombs’ tests are usually negative unless the HUS is due to infection with S. pneumoniae. 53 Osmotic fragility and red blood cell enzyme activity are normal. The life span of infused red blood cells is shortened. The platelet count varies from low normal to markedly decreased and may be less than 20 x 109/L. The survival time of platelets is shortened to between 1.5 to 5.0 days (normal, 7-10 days).@ The duration of thrombocytopenia usually ranges from 7 to 14 days. The mean platelet volume is usually increased. This is an indicator of accelerated platelet formation with release of immature platelets, especially in those individuals who have a platelet count that is not markedly decreased. An increased number of megakaryocytes is seen on bone marrow smears. A leukocytosis with a shift to the left is common.64 The prothrombin time may be prolonged and fibrinogen degradation products are elevated in a significant number of patients. The partial thromboplastin time is usually normal. Laboratory evidence of renal involvement in-

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FIGURE 2 Schistocytes, helmet cells, and red blood cell fragments in a peripheral blood smear.

eludes an elevated serum concentration of creatinine and urea and abnormal findings on urinalysis. Gross hematuria is present in approximately 10% of patients,ll while microscopic hematuria is present in most patients. Pyuria is common. Hyaline, granular, and epithelial casts may also be present. Nonselective proteinuria is a constant finding in the acute stage. Hemoglobinuria is present in patients with severe hemolysis. Metabolic acidosis and hyponatremia are common. Hyperkalemia may be present and is due to acute intravascular hemolysis, acute renal failure, or both. More often, patients are hy okalemic. Hyperuricemia is a common finding P22 and likely results from one or more perturbations of uric acid metabolism including increased release from immature red blood cells due to hemolysis, increased production, alterations in renal function including a decrease in GFR, and possibly increased tubular reabsorption of uric acid.‘22 Serum lactate dehydrogenase is usually markedly elevated. Cardiac enzymes such as glutamicoxaloacetic transaminase and creatine phosphokinase may be elevated if there is myocardial damage. Serum glucose, amylase, and lipase levels may be elevated if there is pancreatic involvement. Because amylase and lipase levels may be elevated due to acute renal failure, *16 pancreatitis is not considered to be present unless the elevations are greater than four times norma1116 or other evidence of pancreatitis is present. During the acute stage, radiographs of the chest may show pulmonary edema. Electrocardiograms (ECGs) may indicate evidence of cardiac dysfunc-

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tion, ischemia, arrhythmias, hyperkalemia, or hypocalcemia. An ultrasound of the kidneys shows a diffuse increase in renal echogeneity characteristic of renal parenchymal disease. Doppler ultrasonography shows decreased blood flow. If pancreatitis is present, an ultrasound of the pancreas may show an increase in pancreatic echogeneity. VTEC can be detected by isolation of the organism from the stool, detection of free fecal SLT, or demonstration of antibodies to VTEC by serologic testing. Although VTEC is believed to be the cause of the majority of episodes of D+ HUS in the Western Hemisphere, VTEC is isolated from the stool of only about 30% of patients with D-t- HUS.” The longer the period of time from the onset of the diarrhea until the stool test, the less likely that VTEC will be isolated.2f Free fecal SLT is detectable in the stool of patients with infection due to VTEC for a longer period than when the actual organism can be isolated. Utilizing this method, VTEC can be identified in about 50% of patients with D+ HUS.‘23 The shorter the duration of time from the onset of diarrhea to the testing for free fecal SLT, the higher the yield. Serologic testing of antibodies to VTEC may provide evidence of infection due to VTEC77 for up to several weeks after the onset of the disease.124 When the combination of stool isolation for VTEC, free fecal SLT, and serologic testing is performed, evidence of infection with VTEC may be found in up to 75% of patients with D+ HUS in North America.123

.

S. dysenteriue type 1, Salmonella species, Y. enterocolitica, and C. jejuni may be identified with conven-

tional stool culture techniques. Oxidase necessary to identify A. hydrophilu.34, 35

testing

is

Pathology Findings The kidneys are the main target organs involved in HUS. Histologic damage in the kidney includes cortical necrosis with predominant glomerular and arteriolar involvement (Fig 3).63 Focal necrosis of glomeruli may also result. Glomerular endothelial cells are a major target of injury in HUS.89* 125 Ultrastructural damage to glomerular endothelial cells is pronounced. The endothelial cells are swollen. In the glomerular capillary loops, the endothelial cells are separated from the basement membrane by an accumulation of material in the subendothelial space. These changes, plus occasional thrombi, lead to occlusion of the glomerular capillary lumina. In contrast to the glomerular capillaries, the endothelial changes in the renal arterioles are associated with a striking deposition of fibrinogen or its derivatives. 12’ At autopsy, microthrombi are found in a number of other organs, including the lungs, heart, liver, adrenals, brain, thyroid, pancreas, thymus, lymph nodes, and ovaries.127 The suggestion that microvascular occlusion causes the extrarenal disease in HUS fails to explain the predilection of the syndrome for the neurologic and renal systems.1*o

Differential Diagnosis Thrombotic thrombocytopenic purpura (TTP) simulates HUS in most of the clinical and laboratory findings, differing mainly in the age of the patient at the onset of the disease and the extent of renal and CNS involvement (Table 2). Some authors, however, consider ‘ITP and HUS to represent a continuum of the same disease. 12* DIC associated with sepsis may present with thrombocytopenia and acute renal failure and may be confused with HUS. However, children with DIC are usually obviously septic with hypotension. In DIC the smear does not always reveal a microangiopathic process and the anemia is not as prominent or may not be present. Coagulation factor analysis, including the partial thromboplastin time and fibrin degradation products, can differentiate the two conditions . Bilateral renal vein thrombosis may be preceded by gastroenteritis that is associated with dehydration and may present with macroscopic hematuria, thrombocytopenia, and acute renal failure.‘29 In renal vein thrombosis, the kidneys are enlarged and the diagnosis can be confirmed by Doppler flow studies or by venacavography of the inferior vena cava. Other differential diagnoses include acute poststreptococcal glomerulonephritis, Henoch-Schonlein purpura, and immune hemolytic anemia and thrombocytopenia. The combination of the characteristic microangiopathic hemolytic anemia, thrombocytope-

FIGURE 3

Typical glomerular involvement in diarrhea-associated hemolytic-uremic syndrome.

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TABLE 2 Differential Features of Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS)

TrP

HUS

Age group Black race Preceding gastrointestinal infection Microangiopathic hemolytic anemia Thrombocytopenia Major neurologic abnormalities Renal abnormalities Fever Hypertension Relapses

Mainly adults Frequent Never

Mainly children Uncommon Common

Severe

Mild to severe

Severe Predominant

Mild to severe Uncommon

Mild to moderate Common Rare Common

Treatment with plasma infusion or plasmapheresis Survival

Beneficial

Predominant 5%-20% 35%~50% Rare, reported only with DHUS Only beneficial in D- HUS

Variable (60%-90%)

> 90% in D+ HUS Variable in D- HUS

D+ = diarrhea-associated;D- = non-diarrhea-associated.

nia, and acute renal failure usually HUS from these other disorders.

distinguishes

Management The active stage of HUS may be defined as that period of time during which there is evidence of hemolysis on the blood smear and the platelet count is less than 100 x 109/L.” The concept of an active stage is useful in the management of patients with HUS. In D+ HUS, the active stage usually lasts an average of 6 days (range, 2-16 days).sc’ It is during the active stage that the complications of HUS per se usually occur. Supportive Care The most important aspect of the treatment of patients with HUS remains excellent supportive care.” Supportive care includes close observation in a tertiary-care pediatric facility; meticulous attention to fluid, electrolyte, and metabolic balance; optimal nutrition; and careful blood pressure control. Children with D+ HUS should be isolated to minimize spread of the bacterial pathogen associated with the diarrhea. Enteric isolation should be maintained until at least one stool culture is negative for the organism. Vital signs such as heart rate, respiratory rate, blood pressure, neurologic status, and temperature should be monitored at least every 4 hours and more frequently if the condition of the child is deteriorating.

24

Current Problems in Pediatrics / January 1993

A clinical assessment of the fluid status is necessary at least twice a day and more frequently in children on peritoneal dialysis. The child should be weighed twice a day as part of the assessment of the fluid status. Accurate fluid intake and output records are necessary to follow the fluid status. Placement of a urinary catheter is important to assess the hourly urine output and to determine the necessary volume of fluid replacement. The hourly urine output is also helpful for determining whether the renal function is improving or deteriorating and whether dialysis is necessary. The urinary catheter should be removed as soon as the urine output is increasing and is greater than 1 .O mL/kg/hr, to minimize the risk of urinary tract infection. If there is no urine output, the catheter should be checked to confirm proper placement in the bladder. The catheter should also be flushed daily to ensure that it is not blocked. The hydration status should be assessed to determine if there is clinical evidence of volume contraction and a prerenal cause for the oliguria. The patient should not be fed by mouth until the diarrhea and vomiting have resolved for a minimum of 24 to 48 hours. Premature attempts to initiate oral feeding are usually unsuccessful. Initial intravenous fluid orders should include dextrose to prevent hypoglycemia, and maintenance amounts of sodium and chloride. No potassium should be added to the intravenous fluid if the patient has oligoanuria. As soon as possible, total parenteral nutrition (TPN) should be initiated to facilitate optimal nutrition. Children with HUS do not tolerate conventional in-

travenous doses of Intralipidn6 because they usually have very high serum triglyceride levels. The serum triglyceride concentration should, therefore, be checked prior to the administration of Intralipid. The serum triglyceride levels should also be followed daily and the Intralipid dose adjusted as necessary. A central venous line may be helpful to allow the delivery of TPN and the collection of blood samples that are important in the monitoring of the biochemical and hematologic status of the patient. The central venous line should be removed as soon as the active stage of the disease is over and the child is tolerating oral feedings. The serum sodium should be determined twice a day during the active stage and more frequently if the serum sodium is low and decreasing. If the serum sodium concentration is less than 130 mmol/L, the sodium concentration in the intravenous fluid should be increased until the serum sodium reaches 130 to 135 mmol/L. This may be necessary several times during the active stage of HUS and is important to minimize the possibility of CNS complications. The serum sodium should not be increased by greater than 0.5 mmoYL/hr. Hyponatremia may also become a problem due to urine losses of sodium during the recovery stage when the urine output increases. The urine concentration of sodium should be measured daily and the intravenous sodium increased appropriately to compensate for the losses in the urine. The serum potassium should be followed twice a day during the active stage. Notwithstanding the acute renal failure, hyperkalemia is not common on admission. If hyperkalemia is present, it should be treated by discontinuing potassium intake, by using cation exchange resins (if they can be tolerated), or by dialysis. If an ECG reveals abnormalities compatible with hyperkalemia, intravenous administration of calcium, sodium bicarbonate, and insulin and glucose are indicated.r3’ Hypokalemia may become a problem as the active stage resolves and the urine output increases. The urine concentration of potassium should be measured daily and the intravenous potassium increased appropriately to compensate for the losses in the urine. The hemoglobin should be checked once a day during the active stage. If the hemoglobin is less than 60 g/L, packed red blood cells should be transfused. A transfusion may be necessary several times during the course of the active stage. Patients with HUS secondary to S. pneumoniae infection should receive washed red blood cells to avoid administration of additional agglutinating antibodies. Platelet transfusions are usually contraindicated because further platelet aggregation may increase

microthrombus formation. Notwithstanding this, platelet transfusions should be considered if the platelet count is less than 10 x 109/L or there is active bleeding. The most common cause of a delay in the recovery or a decrease in the platelet count after a sustained rise is an infectious complication. This may be the first clue to a bacteremia or urinary tract infection. The serum amylase and lipase levels should be measured periodically during the active stage of the disease. If levels are elevated, an ultrasound of the pancreas should be obtained to look for further evidence of pancreatitis. If pancreatitis is diagnosed, the child should be maintained on TPN until the active stage of the HUS is over and the levels of lipase and amylase are falling. It is not necessary to wait until these enzyme levels are normal to resume oral feeding. If vomiting develops with refeeding and the serum levels of amylase and lipase are noted to increase, oral feeding should be discontinued for several days and TPN reinstituted. When hyperglycemia is detected in a patient on peritoneal dialysis, the dialysis prescription should be changed to maintain a constant glucose load and insulin should be administered either intravenously or in the dialysate in a dosage sufficient to maintain a normal blood glucose concentration. ‘I7 If seizures develop, the airway should be secured and an anticonvulsant such as phenobarbital or diphenylhydantoin should be administered intravenously. Measurements of free phenytoin are required for monitoring serum levels accurately because the protein binding of henytoin is decreased in patients with renal failure. El If the child is comatose or there is a deteriorating level of consciousness, a neurologic evaluation should be obtained. If increased intracranial pressure is suspected, methods to monitor and treat the increased intracranial pressure should be employed. Rectal prolapse may occur in a patient with D+ HUS who still has diarrhea. The rectal prolapse must be reduced promptly with a gloved and lubricated finger. This should be performed as often as necessary until the diarrhea resolves. If the patient develops vomiting with initiation of oral feedings after the active stage has resolved and there is no biochemical evidence of pancreatitis, a colonic stricture is a possibility and a barium enema and upper gastrointestinal and follow-through series should be ordered to look for this complication. A stricture may require surgical excision. Hypertension should be treated by removing any excess extracellular fluid from patients on dialysis, and with pharmacologic agents if fluid removal alone is not sufficient or possible. Since the plasma

Current Problems in Pediatrics / January 1993

25

renin activity may be elevated in patients with HUS,“’ converting enzyme inhibitors (captopril, enalapril) should be used. Infections may occur at the site of an indwelling catheter in the bladder, blood, or peritoneal cavity. A urine specimen for routine and microscopy study, a dialysate cell count, and a complete blood cell count including a differential should be obtained daily while the patient has an indwelling urinary, peritoneal, or central venous catheter. Appropriate cultures should be obtained if there is any evidence of infection. Dialysis Early institution of peritoneal dialysis is an important factor affecting immediate survival.13 The most common indications for the initiation of dialysis are to remove enough fluid to allow optimal TPN, and to maintain metabolic balance in an anuric patient. Dialysis may be necessary for the management of hyperkalemia or encephalopathy secondary to uremia. Peritoneal dialysis or hemodialysis can be employed. Arteriovenous hemofiltration may be necessary if fluid overload is a prominent presenting feature. Dialysis can be discontinued once the active stage is over and the urine output is sufficient to maintain a reasonable volume and electrolyte statUS.

Anticoagulant and lkombolytic Therapy Heparin, fibrinolytic agents (streptokinase and urokinase), aspirin, and dipyridamole are unhelpful in the treatment of HUS.13, 132-135 Pharmacologic Therapy Corticosteroids,9 vitamin E,136 furosemide, and captopriI 137 do not affect the outcome of HUS. Plasma Therapy Following the hypothesis that the plasma or serum of patients with HUS may be deficient in factors that minimize, or have tiers that promote plateletendothelial cell interaction, numerous patients have been treated with the infusion of fresh plasma with the aim of minimizing platelet aggregation. However, most reports do not suggest any benefit from plasma infusion in patients with D+ HUS.‘38-140 Rizzoni and colleagues conducted a multicenter controlled trial in 32 children with HUS.‘38 Seventeen children received plasma and 15 received only symptomatic therapy. There were no differences in blood pressure, proteinuria, or hematuria at the end of follow-up. 138Prolongation of acute renal failure in

26

Current

Problems

in Pediatrics

/ January

1993

patients with HUS treated with plasma infusion has been reported. 140This may be due to an alteration in the colloid oncotic pressure or tubulointerstitial injury due to protein overload.140 Loirat and coworkers conducted a multicenter randomized controlled trial on the use of plasma in the treatment of childhood HUS . ‘*’ They concluded that plasma infusions were beneficial because diffuse cortical necrosis was present in seven patients in the control group but was absent in the plasma-treated group. The serum creatinine levels were higher in the control group at 3- and 6-month follow-ups, and the prevalence of proteinuria was also higher in the control group at 6-month follow-up. However, the differences were no longer significant after 1 year.‘*l It has been estimated that a controlled study with at least 350 children is needed to determine conclusively if there is any therapeutic benefit to plasma infusion.23’ 142 In contrast to patients with D+ HUS, patients with D- HUS may benefit from plasma infusion or plasmapheresis. We reported on a child with DHUS who was successfully treated with plasand coauthors also mapheresis. 143 Chintagumpala reported immediate improvement after the infusion of fresh-frozen lasma in two children with chronic relapsing TTP. 98 Plasma infusions are contraindicated in patients with HUS who have a positive direct Coombs’ test result or who are known to have infection due to S. pneumoniae. 53, 65 Plasma contains anti-T IgM antibodies that may worsen the disease in this subset of patients.53 Immunoglobulin Therapy Conflicting results have been reported with immunoglobulin preparations.75, 144 A larger controlled study is necessary to assess the usefulness of this therapy.75 The theoretic basis of immunoglobulin therapy is to neutralize SLT.‘45 Sheth and associates reported that treatment with intravenous immunoglobulin (IVIG) improved the thrombocytopenia, urine output, and serum creatinine in eight children with D+ HUS.l” We reported on nine children with D+ HUS who were treated with IVIG and a control group of nine children with D+ HUS who did not receive this treatment.75 The use of IVIG did not appear to have a beneficial effect. Only one child demonstrated an increase in the platelet count and a decrease in the WBC count within 24 hours of receiving the first dose of immunoglobulin.75 IVIG may not be helpful because commercially available immunoglobulin preparations do not neutralize SLT2.75 SLT may bind rapidly to endothelial cells so that no circulating SLT is available for neutralization by IVIG.75

during the course of HUS, an antibiotic may be necessary to treat an infectious complication.3 It is possible that antibiotics directly affect the production of SLT by bacteria151 or result in the release of SLT when bacteria are killed. Karch and coauthors reported that subinhibitory concentrations of trimethoprim-sulfamethoxazole increased the total yield of SLT produced by S. dysenteriue type 1 and VTEC. 15*

Education and Psychological Support of the Family An understanding of the illness, including the expected clinical course and the potential complications, will usually help a family to deal with this powith a social tentially fatal illness. Consultation worker or a psychologist is often necessary to assist the family in coping with the illness. Public Health Aspects In many jurisdictions, HUS and hemorrhagic colitis due to VTEC are reportable diseases. The role of the public health department is to follow up close personal contacts of the child. Day care, kindergarten, and school officials should be notified, and any individual with close exposure to a child with illness due to VTEC should have a stool test for VTEC. Individuals who develop diarrhea should be assessed by a physician, with a history, physical examination, urinalysis, and blood tests for complete blood cell count, blood smear, and serum creatinine and urea levels.

Prognosis The prognosis in D+ HUS is better than that observed in D- HUS.23 Familial D- HUS has a poor prognosis. The mortality rate is greater than 90% in those patients with the autosomal dominant form and 70% in those with the autosomal recessive form.4 The mortality rate in patients with HUS has fallen progressively from 100% in the original report by Gasser and colleagues, to less than 10% during the last decade (Fig 4).l, 3, ‘** ‘06, 14*, 147 In undeveloped countries, however, the mortality rate is still as high as 72%.15* We reviewed the causes of death in children with HUS.3 CNS complications were the most frequent cause of death and were noted for 47% of all the specified deaths. Other causes include cardiovascular complications, gastrointestinal complications, sepsis, and shock (Fig 5).3 Sudden unexplained deaths are frequently reported. The following factors are reported to be associated with a poor prognosis in D+ HUS:

Contraindications The use of antidiarrheal medications appears to increase the duration of hemorrhagic colitis and the risk for HUS.18, *16, 146 There are reports of an adverse effect,“j* 30* 147 no effect,‘48 and a positive effect”, 1&l 149 of the use of antibiotics in the treatment of hemorrhagic colitis due to VTEC and S. dysenteriue type 1. The specific antibiotic, the sensitivity of the organism to the antibiotic, and the timing of the use of the antibiotic are important variables to consider when assessing whether an antibiotic has any effect.15’ Until this issue is clarified, it is suggested that children with hemorrhagic colitis caused by VTEC should not be treated with an antibiotic. Notwithstanding this,

Elevated WBC count”, aof ‘l, 153 Prolonged anuria”’ Severe prodromal illness154 Severe hemorrhagic colitis with rectal prolapse,154 or colonic gangrenen3 Severe multisystem involvement’27

-

20i

L-

0

1955

FIGURE 4 Reported mortality

1956

1 1973

7 1978 YEXVOfRt?pOft

of hemolytic-uremic

5

5

1980

1988

syndrome

~

in developed

Current

Problems

4

-

Percent

1991

countries,

1955 to 1991.

in Pediatrics

/ January

1993

27

6% Cadiolfascular

6% Shock

6% Gastrointestinal

13% Other FIGURE 5 Causes of death in patients

with

Renal Sequelae in Patients

No. of Children Followed

Authors Gianantonio et al.” Siegler et al.lm Van Dyck et a1.‘57

124 ii

NR = not reported; GFR = glomerular

28

Current

Mean Follow-up W NR 9.6 10.0

Problems

/ January

with

1993

syndrome.

Hemolytic-Uremic

Range of Follow-up W) 5-13 5-18 NR

filtration rate.

in Pediatrics

hemolytic-uremic

the duration of anuria, the less the recovery in GFR that can be expected.“’ Long-term sequelae such as end-stage kidney disease, a reduced GFR, proteinuria, and hypertension develop in a substantial proportion of patients (Table 3). Progressive disease may follow moderate or even mild forms of HUS.‘l Some patients may show a late decline in renal function or become hypertensive. We reported that proteinuria correlates with a poorer outcome in children with D+ HUS.156 Children with proteinuria had a significantly decreased follow-u GFR compared to those without proteinuria. 1% Other authors have also noted the ro ostic significance of persistent proteinuria. P57-gn59 Van Dyck and colleagues reported that the most common renal abnormality in follow-up was a defect in urinary concentration, found in 17% of patients.‘57 de Jong and coauthors reported that patients with a normal GFR 2 years after the acute illness occurred maintained a normal GFR at 10 years of follow-up. 160 Binda ki Muaka and associates studied 45 children with HUS and found that no second-

The most consistently observed poor prognostic feature is an elevated WBC count on admission. 16, 80, ‘l, 153 Hypocomplementemia may also be a poor prognostic feature.‘55 We retrospectively studied 68 children with D-t HUS. There was a statistically significant association between the WBC count and the serum level of the third component of complement (C3). Children with both a low serum C3 level and an elevated WBC count were significantly younger and required hos italization for a significantly longer period of time. P55 Other reported poor prognostic features include a prolonged duration of elevated WBC count,80 thrombocytopenia,80 or anuria. ao, lo1 Numerous authors have noted an association between the duration of anuria and the renal outcome in patients with HUS. 9* *l, 13’~lo1 We studied the relationship of the duration of anuria to the recovery in GFR in 21 children with D+ HUS.r” A significant relationship was found and regression analysis revealed that y = 114.61 - 5.68x, where y is the predicted GFR (in mL/min/l.73 m2) and x is the square root of the duration of anuria (in days). The longer TABLE 3 Follow-up Data on Long-Term

wis

/

16% suddeil,not explained

Syndrome

Decreased GFR (%) 41 28 7

Proteinuria (%) 32 30 11

Hypertension (%I 15 16 7

ary deterioration of renal function occurred once the patients regained a normal creatinine clearance rate. 15’ Recently, several studies demonstrated longterm reduced renal functional reserve in the majority of patients with a history of HUS. Perelstein and coworkers found an abnormal renal functional reserve in 17 children with a history of HUS.161 Tufro and colleagues measured renal functional reserve in 16 children an average of 6.6 years following an episode of HUS. 16’ Inulin clearance values were significantly reduced in patients with HUS compared to controls (59.5 + 9.2 versus 102.7 +- 12.4 mL/min/1.73 m2, P < .025). Acute protein loading was accompanied by an increase in inulin clearance in only 8 (66%) of the 12 patients studied. Notwithstanding these findin s all the children had a normal serum creatinine.i6 !v The clinical significance of the long-term renal complications is unclear. Since the longest re orted average duration of follow-up is 10 years,‘57, Pa the lifetime renal effects subsequent to an episode of HUS are unknown. However, it is generally considered that if at a l-year follow-up, a patient has a normal blood pressure and serum creatinine and does not have proteinuria, the long-term prognosis for preservation of renal function is very good. CNS sequelae include mental retardation, epilepsy, focal motor deficit, optic atrophy, cortical blindness, and learning and behavioral problems. 163 Diabetes mellitus and pancreatic exocrine insufficiency can persist in patients who had evidence of insulin deficiency or pancreatitis during an episode of acute HUS.iti

Follow-up Once the active stage of HUS is over, the urine output has normalized, and the child is tolerating a full diet, the child may be discharged and followed as an outpatient. The family should be counseled to offer a diet that is low in salt, to minimize the risk for hypertension; high in iron and folic acid, to aid in the recovery of the anemia that is present to a variable degree in every patient on discharge; and high in calories, to help the child to regain any loss in weight, which is common, particularly if the illness was prolonged. Children who had a urinary catheter placed should have a urinalysis and culture performed 1 week after discharge to look for evidence of urinary tract infection. The blood hemoglobin should be checked 1 month after discharge, at which time it should be greater than 100 g/L. The recovery in GFR proceeds for approximately 3 to 6 months after an

acute episode of HUS. The more prolonged the period of oligoanuria, the longer it takes for the GFR to recover. After hospitalization for HUS, the child may experience sleep-related or behavioral problems, the majority of which resolves within several months of the acute illness. Children with hypertension, proteinuria, or a decreased GFR should have an assessment at least once a year, including a physical examination, urinalysis, and blood tests for serum creatinine and urea.

Future Therapeutic and Preventive Strategies Because the two principal modes of transmission of VTEC are person-to-person spread and the ingestion of contaminated beef products, prevention may be achieved through public education regarding the necessity of thoroughly cooking hamburger and other beef products, avoiding consumption of unpasteurized milk, and meticulous attention to modern enteric precautions. Patients with known infection due to VTEC should be isolated until stool test results are negative, and persons involved in the care of these patients should wash their hands carefully and dispose of diapers or other soiled garments properly. Protection from infection due to VTEC in humans may be conferred by acquired immunity to either a specific LPS or SLT. 77 A vaccine to revent infection by VTEC is a theoretic possibility. r 7, 123 Because most patients with D+ HUS in developed countries have a complete recovery with supportive care, specific therapies may only be required in those children with more severe involvement.13i Methods to interfere with the adhesion of neutrophils to endothelium by means of early treatment with monoclonal antibodies of specific peptides that block either SLT action, WBC adherence, or cytokine action may have important therapeutic implications in the future.@

Summary HUS is one of the most common causes of acute renal failure in childhood. D+ HUS is the most common form and usually follows an episode of hemorrhagic colitis due to VTEC or S. dysenferiue type 1. The SLT elaborated by these organisms is responsible for the endothelial damage that is the initial insult in the pathogenesis of the acute renal failure. Excellent supportive care is necessary to reduce the mortality and morbidity due to HUS. Current Problems in Pediatrics / January 1993

29

Acknowledgments The authors would Iike to thank Mrs. Heather Sol for expert secretarial assistance, Dr. Alfred0 Pinto for providing Figure 2, and Mr. Sulakhan Chopra of the University of Calgary medical Iibrary for help in the preparation of this manuscript.

21.

22.

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children: A serious hazard of undercooked beef. Postgrad Med 1990; 55:135-142. Milford DV, Taylor CM, Guttridge B, et al: Haemolytic uraemic syndromes in the British Isles 1985-8: Association with verocytotoxin producing Escherichia co/i. Part 1: Clinical.and epidemiological aspects. Arch Dis Child 1990; 65:716-721. Ish-Shalom N, Arbus GS, KarmaIi MA, et al: Clinical and prognostic features of verotoxin (VT)-producing E coli (VTEC)-associated hemolytic uremic syndrome (HUS), in International Symposium and Workshop on Verocytotoxin-producing Infections, Toronto, 2987. Abstract HUS-11. Trompeter RS, Schwartz R, ChantIer C, et al: Haemolyticuraemic syndrome: An analysis of prognostic features. Arch Dis Child 1983; 58:101-105. Robson WLM, Fick GH: Increased incidence of hemolytic uremic syndrome in children who have a father who is either a physician or a lawyer. Pediatr Nephrol 1990; 4:576. Gianantonio CA: Hemolytic-uremic syndrome, in Edelmann CM Jr, Barnett HL, Bernstein J, et al (eds): Pediatric Kidney Disease. Boston, Little, Brown and Company, 1978, pp 724-

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Riley LW: The epidemiologic, clinical, and microbiologic features of hemorrhagic colitis. Annu Rev Microbial 1987; 41:383-407. 38. RiIey LW, Remis Rs, Helgerson SD, et al: Hemorrhagic colitis associated with a rare Escherichia coli serotype. N Engl J Med 1983; 308:681-685. 39. Ryan CA, Tauxe RV, Hosek GW, et al: Escherichia coli 0157:H7 diarrhea in a nursing home: Clinical, epidemiological, and pathological findings. J Infect Dis 1986; 1X631-638. 40. Pai CH, Gordon R, Sims HV, et al: Sporadic cases of hemor37.

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rhagic colitis associated with Escherichiu coli 0157zH7. Ann Zntern Med 1984; 101:738-742. Brown CB, Clarkson AI’, Robson JS, et al: Haemolyticuraemic syndrome in women taking oral contraceptives. Lancet 1973; 1:1479-1481. Venkat KK, Thach D, Kupin W, et al: Reversal of cyclosporme-associated hemolytic uremic syndrome. Trunspht Pm 1991; 23:1256-1257. Verweij J, van der Burg ME, Pinedo HM: Mitomycin Cinduced hemolytic uremic syndrome. Six case reports and review of the literature on renal, pulmonary and cardiac side effects of the drug. Rudiother Oncol 1987; 833-41. Cracker J, Jones EL: Haemolytic-uraemic syndrome complicating long-term mitomycin C and 5-fluorouracil therapy for gastric carcinoma. ] CZin Puthol 1983; 36:24-29. Harris DCH, Lawrence S, Bradstock KF, et al: Intraglomerular thrombosis with deoxycoformycin-Reversible acute renal failure. CZin Nephrol 1984; 21:194- 196. Gardner G, Mesler D, Gitelman HJ: Hemolytic uremic syndrome following cisplatin, bleomycin, and vim&tine chemotherapy: A report of a case and a review of the literature. Ren Fail 1989; 11:133-137. Gottschall JL, ElIiot W, Lianos E, et al: Quinine-induced immune thrombocytopenia associated with hemolytic-uremic syndrome: A new clinical entity. Blood 1991; 77:306310. Sharman VL, Goodwin FJ: Hemolytic uremic syndrome following chicken pox. CZin Nephrol 1980; 14:49-51. Ray CG, Portman JN, Stamm SJ, et al: Hemolytic-uremic syndrome and myocarditis: Association with coxsackievirus B infection. Am J Dis Child 1971; 122:418-420. O’Regan S, Robitaille I’, Mongeau J-G, et al: The hemolytic uremic syndrome associated with ECHO 22 infection. CZin Pediutr 1980; 19:125- 127. Chan JCM, Eleff MG, Campbell RA: The hemolytic-uremic syndrome in non-related adopted siblings. ] Pediutr 1969; 75:1050-1053. Shashaty GC, Atamer MA: Hemolytic uremic syndrome associated with infectious mononucleosis. Am ] Dis Child 1974; 127720-722. Mettler NE: Isolation of a Microtutobiote from patients with hemolytic-uremic syndrome and thrombotic thrombocytopenit purpura and from mites in the United States. N Engl ] Med 1969; 281:1023-1027. Feld LG, Springate JE, Darragh R, et al: Pneumococcal pneumonia and hemolytic uremic syndrome. Pediatr Znfect Dis ] 1987; 6:693-695. Ferriero DM, Wolfsdorf JI: Hemolytic uremic syndrome associated with Kawasaki disease. Pediatrics 1981; 68405-406. Andreoli SE’, Bergstein JM: Acute rhabdomyolysis associated with hemolytic-uremic syndrome. ] Pediutr 1983; 103:78-80. Gradus D, Rhoads M, Bergstrom LB, et al: Acute bromate poisoning associated with renal failure and deafness presenting as hemolytic uremic syndrome. Am ] Nephro2 1984; 4:188-191.

58. Segonds A, Louradour N, Sue JM, et al: Postpartum hemolytic uremic syndrome: A study of three cases with a review of the literature. CZin NephroZ 1979; 12229-242. 59. Herbert D, Kim EM, Sibley RK, et al: Post-transplantation outcome of patients with hemolytic-uremic syndrome: Update. Pediatr Nephrol 1991; 5:162-167. 60. Chavers BM, Wells TG, Burke BA, et al: De novo hemolytic uremic syndrome following renal transplantation. Pediutr Nephrol 1990; 4:62-64. 61. Juckett M, Perry EH, Daniels BS, et al: Hemolytic uremic

syndrome following bone marrow transplantation. Bone MarTransplant 1991; 7:405-409. 62. Loomis LJ, Aronson A], Rudinsky R, et al: Hemolytic uremic syndrome following bone marrow transplantation: A case report and review of the literature. Am ] Kidney Dis 1989; row

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63. Fong JSC, de Chadarevian JP, Kaplan BS: Hemolytic-uremic syndrome. Current concepts and management. Pediutr CZin North

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