Hemolytic uremic syndrome

Overview: What every practitioner needs to know

Are you sure your patient has hemolytic uremic syndrome? What are the typical findings for this disease?

Hemolytic Uremic Syndrome [HUS] is defined by the almost simultaneous onset of acute renal failure, acute hemolytic anemia with fragmented erythrocytes and thrombocytopenia. The most frequent type of HUS is associated with a history of diarrhea that is usually bloody. This is usually caused by Shiga-toxin [Stx] producing E. coli 0157:H7 and is called STEC-HUS or EHEC-HUS. This was previously called Diarrheal {D+] HUS.

Less often, HUS is the result of a genetic mutation (atypical HUS) or infection with invasive S. pneumoniae (Sp-HUS). These were previously called Non-Diarrheal (D-) HUS.

Typical findings in all types of HUS:

Acute renal injury (acute renal failure) with elevated serum creatinine concentration, hematuria and proteinuria.

Acute hemolytic anemia with fragmented red blood cells (schistocytes) on the peripheral smear.

Thrombocytopenia.

The most common symptoms are sudden onset of pallor, change in urine output, edema.

Next most common symptoms are malaise, seizures.

STEC-HUS

– Most cases of diarrheal HUS are caused by E coli 0157:H7.

– In South Asia, most cases are caused by S dysenteriae serotype 1.

– E coli 0157:H7 is the most frequent cause of epidemics of HUS.

– The main reservoir for STEC is bovine.

– Contamination of many vehicles besides ground beef.

– Most children recover from STEC-HUS.

– E coli 0157:H7 urinary tract infection is a rare cause of STEC-HUS.

– The risk for developing HUS in a child under 10 years infected with E coli 0157:H7 is 5 to 15%.

– STEC-HUS occurs mainly in children, but also in any age-group.

The most common type of HUS (>90%) is caused by Shiga-toxin producing E coli, especially E coli 0157:H7 (STEC-HUS).

The key symptoms and signs ofSTEC-HUS are

Sudden onset of pallor a few days after cessation or improvement of diarrhea.

This is often followed by edema, mild icterus, petechiae or even seizures.

There is almost simultaneous onset of anemia and thrombocytopenia, and acute renal injury.

Overt bleeding is uncommon, except in the stools.

There may be hypertension.

Gastrointestinal features

Symptoms-

• Resemble ulcerative colitis, appendicitis, intussusception, gastroenteritis, or acute bacterial enterocolitis.

• Abdominal pain, emesis, diarrhea, bloody and mucoid stools.

Prodromal illness of gastroenteritis –

• Lasts 1 to 14 days.

Colon is the focus of gastrointestinal injury.

• Sigmoidoscopy is rarely indicated – shows friable mucosa, petechiae, ulcers, thick bowel wall.

• Acute colitis is usually transient.

Complications –

• Rectal prolapse, toxic megacolon, bowel wall necrosis, bowel perforation, and gangrene.

Hepatomegaly is common.

Abdominal plain film –

• This may show colon gas accumulation, bowel wall thickening.

Barium enema –

• Rarely indicated.

• May be normal.

• Thumb printing, pseudotumor, transverse ridging.

Labs –

• Elevated liver enzymes, elevated LDH, hypoalbuminemia.

Gallstones –

• May occur after resolution of HUS.

Pathology –

• Thrombosis of submucosal and intramural vessels.

• Mucosal ulceration.

• Pseudomembranes.

Renal manifestations

Urine output – Oliguria in 50% of cases.

Often anuric.

Non-oliguric renal failure in some cases (normal or increased urine output despite rising serum creatinine concentration).

Urinalysis –

Hematuria – microscopic or macroscopic.

Proteinuria is frequent.

Blood pressure –

May be normal.

May be elevated, especially after blood transffusions.

May develop hypertensive encephalopathy.

Fluid overload –

Results in edema, hypertension, cardiac failure.

Labs –

Elevated serum levels of BUN, creatinine, potassium, phosphorus, hydrogen ion, uric acid.

Serum potassium may initially be low.

Low serum bicarbonate, calcium, serum sodium. Low serum albumin.

Elevated serum cholesterol, triglycerides.

Pathology –

Endothelial cell injury, glomerular thrombi, arteriolar thrombi, tubular necrosis.

Pancreas

Acute pancreatitis –

Elevated serum amylase, elevated serum lipase.

Pancreatic islet cell necrosis –

Hyperglycemia, low insulin levels.

Hematologic changes

Anemia –

Mild to severe.

No correlation between severity of hemolysis and severity of renal failure.

Recurrent episodes of hemolysis in first few weeks.

Fragmented erythrocytes on peripheral blood smear.

Anemia aggravated by loss of blood in stools and repeated blood-drawing.

Labs – elevated LDH, reticulocytosis, elevated bilirubin, decreased haptoglobin, negative Coombs’ tests.

Leukocytosis –

This occurs at the onset of HUS.

Related to toxemia and not to systemic infection.

May be a poor prognostic feature in the acute phase.

Thrombocytopenia –

Lasts for up to 2 weeks.

No relationship to disease severity.

Immature platelets on blood smear.

Reduced half-life of platelets – taken up by spleen and liver.

Reduced platelet aggregation.

Increased serum platelet factor 4 and serotonin.

Coagulation factors –

Usually normal.

D-dimer may be increased.

Neurologic manifestations

Major neurologic dysfunction in a third of cases; may be the presenting feature; may determine outcome.

Symptoms –

Irritibility, somnolence, behavioral changes, restlessness, ataxia, tremors, twitching.

Seizures – focal or generalized.

Infrequently – combinations of hemiparesis, decerebrate or dystonic posturing, stupor, coma.

CNS injury caused by Shiga toxin; aggravated by hyponatremia, hypocalcemia, accelerated hypertension.

Onset of neurological manifestations may occasionally occur in convalescence.

Computerized tomography scans may be normal, or may show hemorrhages.

Magnetic resonance imaging may be more sensitive for early detection of lesions.

Pathology – brain edema, microthrombi.

Cardiopulmonary complications

Usually result from fluid overload.

May have myocarditis; cardiogenic shock from microthrombi, cardiomyopathy, aneurysms.

Adult respiratory distress syndrome occurs rarely.

Terminology

The HUS is a Syndrome that includes:

STEC-HUS ([Diarrheal HUS, D+ HUS)

Atypical HUS (D-HUS)

S pneumoniae HUS

Thrombotic thrombocytopenic Purpura (TTP)

TTP shares overlapping features with HUS

Thrombotic microangiopathy (TMA)

This is an all-encompassing histopathological term to describe the lesions in these types of HUS/TTP.

A more stringent definition for STEC-HUS:

Absence of another cause of coagulopathy such as septicemia

Packed cell volume of less than 30%

Fragmented erythrocytes

Platelet count of less than 150,000/cmm

Serum creatinine concentration above the upper limit for age

What other disease/condition shares some of these symptoms?

Atypical HUS

S pneumoniae HUS

Thrombotic thrombocytopenic purpura

Systemic lupus

Antiphospholipid syndrome

Atypical HUS

Onset is often insidious.

May present after non-specific viral infection.

May present with nephrotic syndrome.

May have non-bloody, “viral” diarrhea.

No defined prodromal illness.

All age groups affected.

Similar intra-familial age of onset.

Relapses can occur before transplantation.

Relapses occur in 60-80% of cases after renal transplantation.

Often have rapid progression to end-stage kidney disease.

Prognosis is poor.

Pathogenesis –

Oligogenic inheritance.

Heterozygous mutations in complement regulatory proteins with complement mutations found in 60% of cases.

Loss of function in a plasma or membrane inhibitor of the alternative complement pathway allows for excessive activation of complement on the endothelium.

Mutation in complement factor H (CFH) in 30% of cases.

Variable number of patients have CFI, CMP or CFHR5 and other complement regulatory proteins.

May be inherited by autosomal recessive or dominant modes.

Management –

Guidelines for the investigation and initial therapy of diarrhea-negative (aHUS) based on opinion.

The guideline proposes urgent and empirical plasma exchange (PEX) with whole plasma fraction for the first month after diagnosis.

Treatment of aHUS –

Patients with CMP mutations do not respond to PEX treatment.

Infusions of fresh frozen plasma (FFP) alone is less effective than PEX.

Use FFP with PEX in doses of 40 to 60 ml/kg per session.

No consensus on frequency of sessions or duration of this treatment.

Eculizumab is a monoclonal humanized anti-C5 antibody.

Eculizumab inhibits the terminal complement cascade.

Encouraging results have been obtained in the use of this agent for treatment of aHUS.

The major disadvantage is the high cost of eculizumab.

Liver transplant has also been used successfully for treatment of aHUS.

S pneumoniae HUS

This is a rare condition – incidence is 0.4 to 0.6%.

Usually in infants and young children.

Definition of a Definite case – have features of HUS in a patient with invasive S. pneumoniae infection, and absence of DIC.

High index of suspicion and early diagnosis are important. Neuraminidase exposes TF-antigen, to IgM antibodies against this cryptantigen.

TF-antigen exposure can be assessed by the peanut lectin agglutinin method.

Serotype 19a has emerged as a major cause in the post-Prevnar era.

Try to avoid using plasma, PEX, or blood products.

Acute mortality rates highest in patients with meningitis.

Outcomes – 12% die in the acute stage, 16% have chronic kidney disease and 10% have end-stage kidney failure.

Thrombotic Thrombocytopenic Purpura

Defined by combinations of fever, thrombopenia, hemolysis, neurological involvement, and renal manifestations.

Neurological disease predominates over renal disease.

Onset is usually insidious, bloody diarrhea is uncommon, and brain involvement predominates over renal disease.

TTP is caused by a genetic disorder of ADAMTS13 deficiency or acquired antibodies to ADAMTS13.

The constitutive disorder occurs mainly in infants and young children.

The acquired disorder occurs mainly in adults and is more frequent in females.

Severe deficiency of ADAMTS13 activity is defined as less than 10%.

Survival is lower in patients with more severe ADAMTS13 deficiency.

Documentation of deficiency is not essential for starting treatment.

Diagnosis of TTP is an indication for PEX.

Early recognition is important – more than two schistocytes on a peripheral blood smear is sufficient to trigger the diagnosis and to initiate treatment.

Treatment –

FFP is used for congenital cases.

Corticosteroids and other immunosuppressive agents plus PEX are used for acquired cases.

Outcomes –

High risk of relapses.

80% survive the acute episode.

Many patients have persistent, minor cognitive abnormalities.

Thrombotic Microangiopathy

TMA is a histopathological description of thrombi in renal arterioles and glomeruli.

Not all cases of STEC HUS have evidence of TMA.

TMA is a term that is often used to encompass HUS and TTP.

TMA is a useful term for patients who develop features of HUS or TTP in association with – bone marrow transplantation, malignancy, HIV infection, systemic lupus, systemic sclerosis.

What caused this disease to develop at this time?

The patient was exposed to STEC.

Ingestion of less than 100 bacteria is sufficient to colonize the colon.

STEC HUS is usually caused by Shiga-toxin producing bacteria.

Shiga-toxin E coli (STEC) is the most frequent organism.

Strains include E coli 0157:H7, 0145, 0104:H4.

Three days after ingesting STEC-contaminated material, an individual develops abdominal pain and diarrhea.

Bloody diarrhea occurs in >90% of STEC HUS cases.

During the phase of hemorragic colitis Stx 1 and/or Stx2 enter the blood stream.

The organism does not colonize the blood – this is a toxemia and not a bacteremia.

The toxemic phase progresses to HUS within a few days.

Predisposing causes of HUS

Infections – especially Shiga-toxin producing E coli, especially 017:H7. also S dysenteriae type 1; S pneumoniae; HIV

Genetic disorders – complement dysregulation especially mutations in complement factor H, I, and other complement factors. Inborn errors of cobalamin metabolism. Antibodies to complement factors H and I

Medications – cyclosporine A, tacrolimus, mitomycin-C, oral contraceptives, quinine, ticlopidine, clopidogrel. OKT3, sunitinib and procedures such as irradiation and drugs such as crack cocaine.

STEC-HUS –

Enlightening points on history:

Diarrhea, ingestion of contaminated food, exposure to contaminated water, livestock.

Most patients are afebrile.

Leukocytes found in about half of fecal samples.

Abdominal pain is greater than in other types of gastroenteritis.

Abdomen is tender.

Defecation is very frequent and very painful.

S pneumoniae HUS –

Enlightening points on history include pneumonia, empyema, meningitis.

aHUS –

Enlightening points on history include a previously affected family member, occurrence associated with pregnancy in a family member.

On physical examination –

There may be pallor, petechiae, purpura, edema, dehydration, hypertension, icterus, hepatosplenomegaly, rectal prolapse.

Laboratory studies that are enlightening –

Elevated serum creatinine, microscopic or macroscopic hematuria, proteinuria, low hemoglobin, fragmented erythrocytes, leukocytosis, low platelet count, elevated LDH, low complement C3.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

In a patient with HUS and diarrhea:

In addition to the laboratory findings listed above, request a stool culture for E coli 017:H7.

Obtain a stool specimen for Shiga toxin.

In a patient with HUS and pneumonia, empyema or meningitis:

Obtain a blood culture, CSF culture or empyema aspirste for S. pneumoniae as indicated by the major symptoms and signs.

In a patient with suspected aHUS:

Obtain serum C3, serum factor H and if there are informative, mutation analysis.

Renal biopsy – this is rarely indicated in patients with diarrhea-associated HUS (STEC-HUS).

Renal histopathological findings –

Light microscopy –

Combinations of glomerular, arteriolar and arterial lesions in varying degrees of severity.

Lesions are mainly glomerular.

Some patients have cortical necrosis.

There is also evidence of Stx-mediated renal tubular injury.

The characteristic glomerular lesion is often focal.

There is endothelial cell swelling and a widened subendothelial space that results in a thickened capillary wall and reduced capillary lumen.

Fibrin-like substances and lipids accumulate in the subendothelial space.

Thrombi occlude capillary lumens.

The mesangium is expanded.

Leukocytes infiltrate glomeruli in specimens examined soon after onset.

There may be crescents and areas of necrosis.

Glomeruli often appear lobulated.

Immunofluorescent microscopy –

Deposits of fibrin, fibronectin, IgM, and C3 along capillary walls in mesangium and subendothelial spaces.

Electron microscopy –

Swollen endothelial cells with prominent nuclei and damaged membrana fenestrata.

Detachment of endothelial cells, formation of subendothelial space.

Accumulation of fibrin, cell fragments, lipids and platelets in subendothelial space.

Swollen podocytes with effaced foot processes.

Diagnostic tests and molecular microbiology for STEC-HUS –

Detection of E coli and Shiga toxin [Stx] –

E coli 0157:H7 is detected by plating of fresh feces on sorbitol-McConkey agar.

E coli 0157:H7 strains cannot ferment sorbitol after over-night incubation on sorbitol-McConkey agar and appear as colorless colonies.

Commercial tests for identification of these and other STEC include direct detection of Stx.

E coli 0157:H7 can be detected at point-of-care with an immunodiffusion card.

Routine laboratory tests –

Frequent tests (may be daily, twice daily or depending on patient’s status, many times a day) –

Hemoglobin, hematocrit, platelet count. white cell count, LDH.

BUN, serum creatinine.

Serum electrolytes, calcium, phosphorus.

Blood glucose.

Helpful but not needed for frequent monitoring –

Urine protein concentration.

Urinalysis.

Liver enzymes, serum albumin, amylase, lipase.

PT, PTT, D-dimer, fibrinogen.

Serum urate.

Confusing tests in STEC-HUS –

ADAMTS13 – may be reduced in any patient with endothelial injury without being diagnostic for TTP or indicating need for FFP or PEX.

Troponin1 may be elevated in acute renal failure. But elevated Troponin1 levels must be taken seriously if there are signs of myocardial injury.

Urine FeNa is of little value in the management of these patients, especially if the patient is not oliguric.

Would imaging studies be helpful? If so, which ones?

In HUS presumed to be caused by E. coli, obtain a plain film of the abdomen for evidence of obstruction, or perforation.

Try to avoid computed tomography (CT) scans of abdomen or barium enemas.

Renal ultrasound an renal doppler studies are generally not helpful.

If S. pneumoniae is suspected, obtain chest x-ray and even chest CT-scan.

EKG and/or ECHO cardiogram when indicated.

Imaging of head rarely yields useful information that can help management.

Avoid gadolinium-containing contrast agents – they can cause Nephrogenic Systemic Fibrosis in renal insufficiency.

Confirming the diagnosis

A clinical decision algorithm is available for suspecting/confirming the diagnosis. The strength of evidence is based on opinion.

The diagnosis of HUS is confirmed by the occurrence of acute renal injury, acute hemolysis and thrombocytopenia.

If there is no antecedent diarrhea, S. pneumoniae HUS must be suspected in the presence of lung or CNS infection.

In the absence of diarrhea or S. pneumoniae infection, aHUS must be suspected.

Recognition of aHUS is outlined in PUBMED:18800230.

If you are able to confirm that the patient has hemolytic uremic syndrome, what treatment should be initiated?

Management of the gastroenteritis:

The vascular injury is under way by the time an affected patient seeks attention for diarrhea – the severity varies.

Affected patients must be hospitalized, isolated, and must be given intravenous fluids carefully.

No antibiotics, NSAIDs, antimobility agents, or opioids.

Encourage hospital admission:

Contact precautions.

Acute intravenous rehydration with normal saline 20 ml/kg:

Use isotonic saline for volume expansion and maintenance.

Do not use hypotonic saline.

Repeat boluses of normal saline [10 to 20 ml/kg].

Reduce fluid volumes –

if urine output is decreasing.

if there are signs of central volume overload.

if the serum creatinine is increasing.

Add potassium to intravenous fluid –

if serum potassium is normal or low.

Monitor carefully if patient is oligo-anuric.

Most patients can eat or drink but fluid volumes must be recorded.

Daily lab tests –

complete blood count

basic metabolic panel.

Avoid prolonged bladder catheterization.

Repeat lab tests day after discharge.

Measures that have been used to prevent acute renal failure and/or HUS –

High doses of loop diuretics –

Not successful.

Volume expansion –

Study suggests that parenteral hydration early during course of STEC infection is renoprotective for children who develop HUS.

Antibiotics –

No current consensus on use of antibiotics in diarrheal phase – however, it is prudent to avoid their use

Sensorb PK –

Diatomaceous silicon diamide compound linked to a dissaccharide fails to prevent extrarenal complications or reduce need for dialysis.

Starfish –

Binds to Stx 1000 times more efficiently than Synsorb PK.

Protects mice against a lethal dose of Stx.

Modified Starfish, Daisy, protects mice against lethal doses of Stx1 and Stx2.

Antibodies to Stx –

Monoclonal antibodies specific for the A subunit of Stx1 prevents lethal complications in mice.

Vaccination -A plant-based oral vaccine protects mice against lethal doses of Stx2.

Specific Treatment

General measures –

Try to avoid bladder catheterization but measure urine output.

Try to weigh patient daily.

Monitor blood pressure with appropriate sized cuff.

Try to avoid arterial catheters,

Monitor carefully all fluid intake and fluid losses.

Restrict fluid at first indication of hypertension, cardiopulmonary overload.

Prefer vasodilators for hypertension treatment.

Adjust doses of renally excreted drugs.

Use narcotics with caution. Their metabolites can cause seizures or obtundation in renal failure.

Elevated Troponin1 during HUS should be attributed to cardiac ischemia rather than renal failure.

Monitor serum potassium carefully.

Restrict phosphate and use phosphate binders if indicated.

Provide adequate calories for age and size, enterally or parenterally.

Provide dialysis patients with appropriate vitamin supplements.

Do not use corticosteroids.

Dialysis –

Indications are similar to those in other types of acute renal failure –

Hyperkalemia (>6.5 mEq/L, EEG changes).

Azotemia is not by itself an indication for dialysis.

Severe metabolic acidosis (bicarbonate < 10 mEq/L).

Hypertension from fluid overload especially if oligoanuric and unresponsive to vasodilators.

Volume overload causing cardiac or pulmonary compromise.

Severe oliguria or anuria.

Oliguria limiting adequate nutritional support, or need for blood transfusions.

No advantages of either peritoneal or hemodialysis.

Hemodiafiltration is useful for “gentle” fluid removal.

No indications for dialysis in polyuric patients (non-oliguric renal failure) despite very high serum creatinine or BUN levels.

Management issues specific to HUS –

Dialysis is generally started soon after onset of anuria.

Continue dialysis until urine output provides adequate clearance of potassium and normal bicarbonates.

Once urine output has re-started, and serum creatinine is decreasing, is no need to dialyze until serum creatinine is normal.

Renoprotection after recovery from acute renal failure –

Angiotensin-converting enzyme inhibitors (ACEi)

– In patients with hypertension and/or proteinuria and/or decreased GFR, ACEi may protect the renal function.

– Blood pressure may normalize.

– Proteinuria may decrease.

Hemolytic anemia –

Hemolysis may occur rapidly and recur rapidly.

Monitor hemoglobin, hematocrit and platelet counts frequently.

For rapidly decreasing hemoglobin, transfuse washed, packed red blood cells slowly over 2 to 4 hours to avoid hypertension.

Transfuse only if hemoglobin falls to below 6 to 7 g/dl.

Add a diuretic if the patient is not on dialysis.

Monitor blood pressures, urine output and cardio-respiratory status to prevent pulmonary edema and/or accelerated hypertension.

Iron therapy is usually not needed bcause iron from hemolysed erythrocytes should be available.

Early erythropoietin treatment may reduce the number of blood transfusions. The evidence is weak but suggestive.

Thrombocytopenia –

Rarely causes bleeding.

Rarely requires infusions of platelets.

Platelet infusions for surgical procedures or active bleeding.

The unproven rationale for limiting platelet infusions is that this may increase risk of microthrombi.

Coagulopathy –

No evidence to support th use of heparin, aspirin, dipyridamole, urokinase, streptokinase, clopdogrel for HUS.

No evidence supporting use of fresh frozen plasma or plasmapheresis in STEC HUS with or without central nervous system involvement. No evidence to support the use of eculizumab in the treatment of STEC HUS.

Immediate therapy –

Blood transfusion if hemoglobin is <6 g/dl.

Volume expansion if volume depleted.

Fluid restriction if fluid overloaded.

Anti-hypertensive agents if severely hypertensive.

Monitor for surgical complications –

Intestinal perforation, bowel necrosis in acute phase especially if acidosis is not easily corrected by dialysis.

Bowel strictures after recovery.

Monitor carefully for –

Central nervous system complications.

Treat seizures appropriately.

Pulmonary consequences of fluid overload, pleural effusions.

Adult respiratory distress syndrome.

Acute pancreatitis.

Diabetes mellitus. Treat hyperglycemia appropriately.

Renal transplantation –

Post-transplant HUS occurs in aHUS, as a de novo event, de novo in association with calcineurin inhibitors.

Post-transplant HUS can be difficult to distinguish from acute ejction or cyclosporin A toxicity.

Post-transplant HUS is very uncommon in patients with STEC HUS.

Chronic peritoneal or hemodialysis.

Chronic ant-hypertensive therapy.

Chronic ACE-inhibitor treatment for proteinuria.

Immediate therapy –

Blood transfusion if hemoglobin is <7 g/dl.

Volume expansion if volume depleted.

Fluid restriction if fluid overloaded.

Anti-hypertensive agents if severely hypertensive.

Monitor for surgical complications –

Intestinal perforation, bowel necrosis in acute phase especially if acidosis is not easily corrected by dialysis.

Bowel strictures after recovery.

Monitor carefully for –

Central nervous system complications.

Treat seizures appropriately.

Pulmonary consequences of fluid overload, pleural effusions.

Adult respiratory distress syndrome.

Acute pancreatitis.

Diabetes mellitus. Treat hyperglycemia appropriately.

Renal transplantation –

Post-transplant HUS occurs in aHUS, as a de novo event, de novo in association with calcineurin inhibitors.

Post-transplant HUS can be difficult to distinguish from acute ejection or cyclosporin A toxicity.

Post-transplant HUS is very uncommon in patients with STEC HUS.

Chronic peritoneal or hemodialysis.

Chronic ant-hypertensive therapy.

Chronic ACE-inhibitor treatment for proteinuria.

What are the adverse effects associated with each treatment option?

Blood transfusions may cause hypertension.

Hemodialysis or hemodiafiltration may be associated with catheter complications such as bleeding, clotting, infection.

Peritoneal dialysis may be complicated by peritonitis.

What are the possible outcomes of hemolytic uremic syndrome?

Prognosis

The acute phase lasts a few weeks and will be like a roller coaster ride with many ups and downs.

Most patients recover.

Fewer than 5% die; in our institution the acute death rate is 1%.

Death is almost always related to extra-renal causes.

Most patients recover without needing future dialysis or transplantation.

Acute prognosis

Patients who do not have oligo-anuria and who do not need dialysis do extremely well.

The longer the period of anuria, the more likely that there will be chronic kidney disease. However, there are many exceptions and even patients with weeks of anuria have done extremely well.

Recovery of kidney function more than likely will be complete.

Some patients have residual proteinuria and/or hypertension but these may improve with time.

Patients who have residual proteinuria and or hypertension can be managed with ACE inhibitors.

In almost every case in whom the serum creatinine is normal after recovery, there will not be progression to end stage kidney disease in the future.

It is extremely unlikely that STEC HUS will recur at a later date.

STEC HUS is not inherited.

Risks/benefits of the available treatment options

There is no debate about the need for each treatment when and where indicated.

No benefits to plasma infusions.

No benefits to plasmapheresis.

Dialysis, when indicated, is life-saving.

Long-term prognosis

A small percentage of patients with STEC HUS will progress to end stage renal failure.

What causes this disease and how frequent is it?

Epidemiology

• Patients are usually healthy prior to onset of acute gastro-enteritis.

• E. coli 0157:H7 causes isolated cases, small clusters of cases and large epidemics of HUS.

• Cases must be reported to local disease-investigation officers.

• Occurs mainly in children between 6 months and 4 years but infants and adults can be affected.

• More than 90% of children with HUS have US caused by STEC.

• Fewer than 50% of adults with HUS have STEC infection.

• Slightly more females than males are affected.

• There is a seasonal incidence with peaks in summer.

• The disease occurs all over the world.

• Clusters of cases occur.

• STEC-HUS in affected siblings occur closely together and may result from a common source of infection or sib to sib transmission.

• Ground meat is not the only cause of STTEC HUS.

• Ground meat must be cooked to a temperature greater than 68 degrees Celsius.

• Recurrent episodes of STEC HUS are extremely uncommon.

• Modes of transmission – Ground beef, Bovine contact, Petting zoos, Airborne transmission, Deer jerky, Salami, Salmon roe, Person-to person contact, Day-care centers, Unpasteurized milk, Municipal water, Swimming pool water, Lettuce, Radish sprouts, Spinach.No genetic factors have been implicated in the pathogenesis of STEC-HUS.

How do these pathogens/genes/exposures cause the disease?

To cause HUS an agent must be able to damage glomerular endothelial cells.

Shiga-toxin-producing E coli (STEC) are also called Verotoxin-producing E. coli (VTEC) as well as EHEC.

The primary virulence factor is Stx2 – All Shiga toxins comprise a single 30 kDa A-sub-unit and a pentamer of non-covalently attached identical 7 kDa B-subunits. Enzymatic activity is in the A-subunit and cell recognition receptor binding properties are in the B-subunits. Stx1 and Stx2 are immunologically distinct. Each does not target exactly the same tissues. But both bind to Gb3 and can cause HUS. Gb3 is the receptor on endothelial cells. Gb3 is expressed in human glomerular endothelial cells, mesangial cells, and tubular epithelial cells. The amount of Gb3 in cells determines their sensitivity to Stx. After Stx binds to Gb3 the complex is transported into the cell, cleaved into an active A1 subunit, and inhibits RNA thereby causing cell death.

During the stage of hemorrhagic colitis the toxins of E. coli 0157:H7 (Stx1 and/or Stx2) enter the blood circulation.

Glomerular endothelial injury results in local intravascular coagulation and mechanical destruction of erythrocytes and platelets by fibrin strands in narrowed vessels.

Platelet adherence contributes to microthrombi formation.

• Summary of pathogenesis – a succession of inter-related, overlapping synchronous and asynchronous events –

  Stx-producing E. coli infection causes colonic injury.

  Stx enter the circulation.

  May be transported on leukocytes.

  Stx attaches to Gb3 receptors.

  This inhibits cell protein synthesis and causes cell injury and death.

  There is also access and interaction with lipopolysaccharide, interleukins tumor necrosis factor.

  Cell death exposes collagen to coagulation factors and platelets.

  There is local activation of coagulation with formation of fibrin thrombi.

  Platelets are activated and are removed by the spleen and liver.

  Endothelial cell functions are perturbed – prostacyclin, von Willebrand factor, endothelin, nitric oxide, PAI-1.

  Endothelial cells are swollen, injured, detached.

  The glomerular capillary lumen is narrowed, glomerular filtration rate is decreased.

  There is also acute tubular injury, obstruction and anuria.

What complications might you expect from the disease or treatment of the disease?

Complications of STEC-HUS

Renal complications:

Chronic renal failure.

End-stage kidney disease.

Hypertension.

Pre-eclampsia.

Proteinuria.

CNS complications:

Acute seizure, encephalopathy, coma.

Rarely, chronic encephalopathy, paresis.

Pancreatic complications:

Acute pancreatitis.

Diabetes mellitus.

Gastrointestinal complications:

Intestinal gangrene.

Rectal prolapse.

Obstruction, perforation.

Chronic strictures.

Cholelithiasis.

Cardio-pulmonary:

Acute cardiogenic failure.

Acute adult respiratory distress syndrome.

Psychological post-traumatic stress for patient and family.

Complications of treatment

Acute peritonitis.

Short-bowel syndrome if colon has been removed because of gangrene.

Vascular injury from dialysis catheters.

Bleeding if anticoagulants were used.

How can hemolytic uremic syndrome be prevented?

The number of E coli 0157:H7 required to cause infection is as low as 100 organisms.

There are no prophylactic drugs or vaccines.

Prevention of STEC HUS

Avoid primary infection with STEC bacteria.

Wash hands thoroughly.

Prevent food cross-contamination.

Do not allow toddlers with diarrhea to go into wading pools.

Cook food well.

Cook ground beef >68 Celsius.

Prevent secondary spread by isolating contacts.

Admit affected/suspected cases to hospital.

Contact precautions – hospitalize in a single room, use gloves at all times, gown while in contact with patient, or any potentially affected surface or object.

Genetic counseling

Not indicated for STEC HUS or S. pneumoniae HUS.

Indicated for aHUS.

What is the evidence?

Bitzan, M, Schaefer, F, Reymond, D. “Treatment of typical (enteropathic) hemolytic uremic syndrome”. Semin Thromb Hemost. vol. 36. 2010 Sep. pp. 594-610. (This manuscript provides an overview of the current treatment options and reviews the supporting evidence.)

Hickey, CA, Beattie, TJ, Cowieson, J, Miyashita, Y, Strife, CF, Frem, JC, Peterson, JM, Butani, L, Jones, DP, Havens, PL, Patel, HP, Wong, CS, Andreoli, SP, Rothbaum, RJ, Beck, AM, Tarr, PI. “Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome”. Arch Pediatr Adolesc Med. vol. 165. 2011 Oct. pp. 884-9. (This article discusses the potential benefit of early volume expansion in treating HUS.)

Lapeyraque, AL, Malina, M, Fremeaux-Bacchi, V, Boppel, T, Kirschfink, M, Oualha, M, Proulx, F, Clermont, MJ, Le Deist, F, Niaudet, P, Schaefer, F. “Eculizumab in severe Shiga-toxin-associated HUS”. N Engl J Med. vol. 364. 2011 Jun. pp. 2561-3. (This case series describes the first experience with the use Eculizumab in severe typical HUS.)

Ongoing controversies regarding etiology, diagnosis, treatment

The recent use of eculizumab to treat adult patients with STEC-HUS may be controversial and a consensus is evolving.

No evidence that eculizumab is indicated in children with STEC-HUS.

The use of FFP with or without PEX for STEC-HUS is controversial.

No evidence supporting the use of FFP with or without PEX in children with STEC-HUS.

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