Haemolytic uraemic syndrome

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16.5 Haemolytic uraemic syndrome

Karen McCarthy

Essentials

1 Diagnosis is based on the presence of microangiopathic haemolytic anaemia, thrombocytopenia and renal impairment.
2 Diarrhoea-associated haemolytic uraemic syndrome accounts for 90% of cases.
3 The cornerstone of treatment is careful attention to fluid and electrolyte balance.
4 Most patients with haemolytic uraemic syndrome have some degree of encephalopathy.
5 Hypertension is present in up to 50%.
6 Long-term follow up is necessary.
7 Use of antibiotics, antimotility agents and non-steroidal anti-inflammatory drugs should be avoided in children acutely infected with Shigatoxin Escherichia coli.

Introduction

Definition

Haemolytic uraemic syndrome (HUS) is the commonest cause of acute renal failure in infants and young children <5 years of age in developed countries. There is multisystem involvement in this syndrome, which is characterised by sudden onset of non-immune microangiopathic haemolytic anaemia, thrombocytopenia and acute renal failure. Various degrees of severity occur. One-third of patients are anuric at presentation.

An inherited form, which is transmitted in an autosomal dominant manner, may present in the newborn period.

Epidemiology

The commonest form of HUS in children is the one that occurs following a prodromal illness of acute gastroenteritis with bloody diarrhoea. This diarrhoea-associated haemolytic uraemic syndrome (D+HUS) accounts for 90% of cases. D+HUS is most often caused by Shiga toxin (verotoxin) producing Escherichia coli (STEC, also called VTEC). Other cytotoxin-producing bacteria such as Shigella dysenteriae type 1, Salmonella typhi and Campylobacter are less common causes of HUS. Streptococcus pneumoniae also causes HUS but does so via a completely different mechanism, which involves neuraminidase rather than cytotoxin production.

D+HUS occurs in epidemics as well as sporadically. Outbreaks can be traced to contaminated food, especially undercooked hamburger and contaminated water.

There are over 100 different serotypes of STEC with different phage typing and subtyping. STEC O157:H7 is the commonest subtype producing disease in North America, the British Isles and Japan. It is rare as a causative agent of HUS in Australia, where other types, including O111:H, are pathogenic. E. coli can be spread by person to person contact. The incubation period to onset of diarrhoea is 1–8 days.

Non-diarrhoeal-associated HUS (D– HUS) cases account for 10% of cases. These are secondary to:

• non-enteric infections, e.g. streptococcal pneumonia;
• immunosuppression: malignancy-associated, following bone-marrow transplant, and drug-related, e.g. mitomycin, ciclosporin and FK-506 (tacrolimus);
• immunodeficiency and pregnancy may also be associated with HUS.

Pathophysiology

The primary process in the pathogenesis of HUS is vascular endothelial cell injury. E. coli is ingested and colonises the gut. These bacteria attach to the epithelium of the distal ileum and large intestine by complex mechanisms. Cytotoxins are produced and they damage the microvasculature of the intestinal wall, causing haemorrhagic and ulcerative intestinal lesions. Once the intestinal–blood barrier has been compromised, the toxins gain entry to the circulation. It is presumed that the toxin then initiates microvascular damage in the glomerular endothelium of the kidneys. Intravascular and intraglomerular fibrin clot is formed and at the same time there is activation of the coagulation system, which leads to occlusion of the vessels and glomerular loss. Erythrocytes passing through these vessels become damaged. Microvascular endothelial cell injury is central to the renal thrombotic microangiopathy that is characteristic of HUS. Thrombocytopenia results from intrarenal platelet adhesion and platelet survival is shortened. Renal dysfunction results from this process.

History

A child who has previously been healthy presents with a history of gastroenteritis within the previous 2 weeks. There is subsequent development of vomiting, bloody diarrhoea and crampy abdominal pain. The child is usually afebrile at presentation. The presentation may resemble an acute surgical abdomen. The child then becomes pale and develops haematuria and oliguria and is noted to become lethargic. Not uncommonly, the patient appears to be improving from his/her gastroenteritis but then deteriorates suddenly, becoming quite ill.

Examination

The child appears pale, lethargic and dehydrated. Petechiae may be noted on the skin, which may also appear jaundiced.

Most patients have some degree of encephalopathy. Central nervous system involvement can range from irritability and restlessness to seizures or coma. Seizures can be present in up to 40%. Hemiparesis and cranial nerve dysfunction may be seen.

Hypertension is present in up to 50% and is likely secondary to increased renin levels. Evidence of cardiac involvement may present as myocarditis, cardiomyopathy or high-output failure. Oliguria occurs often. Hepatomegaly and oedema develop (reflecting fluid overload) if the oliguria is not recognised and fluid intake is not restricted. Splenomegaly is not as common as hepatomegaly.

Investigations

Diagnosis of HUS is based on the presence of microangiopathic haemolytic anaemia, thrombocytopenia and renal failure.

• Anaemia is usually severe and is normochromic normocytic in type with a haemoglobin level of 50–90 g L–1.
• White cell count is non-specific and often raised with increased number of immature forms.
• Platelet count is low in 95% and can be as low as 20 × 109 L–1. Subsequent increase in platelet count may be the first indication of resolution of the microangiopathic process.
• Reticulocyte count is mildly elevated.
• Evidence of schistocytes, burr cells and helmet cells on blood film.
• Coombs test is negative – indicating anaemia is not immunologically mediated.
• Coagulation tests are usually normal but may show mild disseminated intravascular coagulation.
• Serum haptoglobin is low, lactic dehydrogenase (LDH) is elevated along with indirect bilirubin level – all indicators of intravascular haemolysis.
• Elevated serum blood urea, creatinine and phosphate reflect renal involvement, occurring at the same time as the urine output is declining and the haemolysis developing.
• High triglycerides.
• High lipase/amylase reflecting pancreatic involvement.
• Low albumin even without nephrosis.
• Electrolyte derangement may result from the renal abnormalities, including hyponatraemia, hyperkalaemia, hypocalcaemia and metabolic acidosis (which can be severe).
• Urinalysis shows haematuria that can be gross and the red blood cells are dysmorphic. There can be evidence of proteinuria (mild to severe) and leucocytes. Granular and hyaline casts may be present.

Renal biopsy is rarely indicated in children who have the characteristic features of HUS.

Differential diagnosis

• Intussusception.
• Disseminated intravascular coagulation (DIC) in patients with sepsis and multi-organ failure.
• Idiopathic thrombocytopenic purpura (ITP).
• Systemic lupus erythematosus (SLE) with nephropathy.
• Leukaemia.
• Toxic syndromes and encephalitis may have similar presentation.
• Post-infectious glomerulonephritis.

Findings on blood film, coagulation profile, urinalysis, stool and blood cultures assist in differentiating all these conditions from HUS. There is no evidence of haemolysis in intussusception. The complete blood count in leukaemia would reveal low haemoglobin, thrombocytopenia and a white cell count that was depressed or markedly elevated with the presence of blasts.

Patients with DIC have sepsis and prolongation of the prothrombin time and partial thromboplastin time. ITP has isolated thrombocytopenia with a normal coagulation profile.

Treatment

There is no specific therapy for Shiga toxin-producing E. coli and prevention of the disease is therefore of utmost importance.

Supportive therapy may include dialysis, antihypertensive therapy, blood transfusions and management of neurological complications. With supportive therapy, 85% of children recover renal function.

The cornerstone of treatment is careful attention to electrolyte and fluid balance. Once intravascular volume has been restored, the amount and type of fluid administered should be limited to ongoing losses, i.e. insensible loss, urine output and gastrointestinal losses.

No added potassium is required unless serum levels are below normal values. Hyperkalaemia must be anticipated and treated in a timely fashion (refer to management of hyperkalaemia in Chapter 10.5 on electrolytes).

Anaemia should be treated with packed red blood cell transfusion (10 mL kg–1) when anaemia is severe, the patient is symptomatic or the haematocrit is falling rapidly. In general, an attempt is made to maintain Hb > 70 g L–1 when possible.

Platelet transfusion is avoided because of precipitous worsening of the patient’s clinical status. This results from the aggregation of platelets, which are a major constituent of microthrombi and thus induce further damage. Newly formed platelets in HUS function very well and platelet transfusion is not required, even prior to the surgical insertion of a central venous catheter or peritoneal dialysis catheter.

Hypertension responds well to treatment with short-acting calcium channel blockers, e.g. nifedipine. Intravenous nitroglycerine can be used if oral medication is not tolerated. Nitroprusside is not favoured because of the danger of cyanide poisoning in renal failure. Labetalol by intravenous bolus or continuous infusion can also be used to manage hypertension (see Chapter 16.3). Treatment of hypertension can prevent development of encephalopathy and congestive heart failure.

Seizures should be treated with short-acting benzodiazepines initially, followed by intravenous infusion of phenytoin or phenobarbital.

There is some evidence that early dialysis may improve outcome in HUS. Dialysis should be commenced in the following situations:

• severe hyperkalaemia uncontrollable by medical means;
• fluid overload and pulmonary oedema;
• significant uraemic symptoms;
• blood urea >36 mmol L–1 even if electrolyte and water balances are satisfactory;
• anuria.

Peritoneal dialysis is generally used in infants and preschool-age children unless there is evidence of severe colitis or abdominal tenderness is present. This management strategy is dependent on the resources and preferences of the managing team/unit.

There are no controlled clinical trials demonstrating efficacy of antibiotic therapy on the prevention and amelioration of HUS. In fact, the use of antibiotics should be avoided in children infected with Shiga toxin E. coli.

There are no controlled randomised studies on plasmapheresis as treatment for D+HUS. Plasmapheresis may be beneficial in patients with drug-induced HUS. Vincristine and ciclosporin A are known to cause drug induced HUS.

Nutritional requirements must be addressed aggressively, as these patients are catabolic and hypoalbuminaemic. Enteral feeds can be commenced once the diarrhoea has settled. Total parenteral nutrition is required in some cases.

No evidence exists for the use of aspirin, heparin, warfarin, streptokinase, urokinase, vitamin E or immunoglobulin G in the treatment of HUS.

Prognosis

Overall prognosis for D+HUS is better than that for D– HUS. However, long-term prognosis for those D+HUS who recover, but have persistent proteinuria 1 year following recovery, is guarded. There is an early mortality rate of about 5%. Another 5% require lifelong dialysis because of the development of chronic renal failure and anuria.

The improved prognosis has resulted from careful correction of electrolyte abnormalities, judicious fluid management and earlier institution of dialysis.

The risk of renal sequelae in children is higher in males, and those with hypertension, prolonged anuria and haemoglobin <100 g L–1 at onset of disease.

Other poor prognostic indicators include:

• elevated white cell count (>20 × 109 L–1) at presentation;
• elevated white cell count at presentation, which remains elevated;
• age < 1 year or > 5 years;
• central nervous system involvement (seizures, coma, etc.);
• the degree and duration of renal dysfunction.

Complications

Children with D+HUS should be followed for many years following full recovery as some long-term studies have shown late complications developing in patients who had fully recovered initially. These complications include hypertension, proteinuria, reduced glomerular filtration rate and late development of end-stage renal disease (ESRD). ESRD was shown to develop in 10–15% as late as 15–25 years following recovery.

The frequency of complications is higher in D– HUS patients.

HUS can recur in transplanted kidneys regardless of the aetiological agent. Recurrence of disease following renal transplant is infrequent in D+HUS in comparison with D– HUS.

Occasionally, children can be left with chronic sequelae due to HUS, which are not renal related. Almost any organ system can be involved. Stroke is the most serious sequela and occurs in 3–5% of patients. Colitis can result in bowel infarction, leading to colostomy/colectomy or stricture formation.

Pancreatitis can develop, sometimes with diabetes, and hepatic involvement can occur.

Prevention

D+HUS is an infectious disease and the most effective prevention strategy would be to prevent ingestion of the E. coli. Avoidance of undercooked meat can assist in this area. There are, however, other vectors for the transmission of the E. coli and these include contaminated water and beverages. Food handlers, vendors and consumers must be made aware of proper food-handling techniques.

Controversies and future directions

In one study, a strategy was developed in which a recombinant E. coli was generated that had on its surface a lipopolysaccharide (LPS), which mimicked the Shiga toxin receptor. These recombinant E. coli bind to the Shiga toxin thus preventing the binding of Shiga toxin to target cells.
Strategies for immunisation have been explored. The first steps in evaluation of development of a vaccine against Shiga-toxin-producing strains of E. coli have been undertaken in a preclinical study.
An oligovalent water-soluble carbohydrate pentamer with five pairs of trisaccharide ligands linked to a central dendrimer, and called ‘Starfish’, neutralises all five B subunits of Shiga toxin and protects human cells from Shiga toxin in culture.
Administration of intravenous γ-globulin IgG and gabexate mesilate, a synthetic serine protease inhibitor used as an anticoagulant resulted in amelioration of disease in five children with D+HUS. The IgG itself has no proven benefit on the course of D + HUS.
The use of angiotensin-converting enzyme inhibitors in conjunction with controlled intake of protein (to recommended daily allowance) may help preserve renal function in children with persistent proteinuria during the chronic stages of Shiga toxin HUS.
New DNA probes to detect Shiga toxin in stool have been developed but are not yet clinically available.

Further reading

Corrigan J.J.Jr, Boineau F. Hemolytic uremic syndrome. Pediatr Rev. 2001;22:365-368.

Cronan K., Norman M. Renal and electrolyte emergencies. In: Fleisher G.R., Ludwig S., editors. Textbook of pediatric emergency medicine. 4th ed. Philadelphia: Lippincott, Williams & Wilkins; 2000:847-848. Chapter 86

Elliott E.J., Robins-Browne R.M., O’ Loughlin E.V., et al. Nationwide study of haemolytic uraemic syndrome: Clinical, microbiological, and epidemiological features. Arch Dis Child. 2001;85:125-131.

Garg A.X., Suri R.S., Barrowman N., et al. Long-term renal prognosis of diarrhoea-associated hemolytic uremic syndrome: a systematic review, meta-analysis and meta-regression. JAMA. 2003;290(10):1360-1370.

Kaplan B., Meyers K. The pathogenesis of hemolytic uremic syndrome. J Am Soc Nephrol. 1998;9:1126-1133.

Ray P., Liu X. Pathogenesis of Shiga toxin-induced hemolytic uremic syndrome. Pediatr Nephrol. 2001;16:823-839.

Ring G.H., Lakkis F.G., Badr K.F. Microvascular diseases of the kidney, 6th edn. Brenner B., editor. The kidney, vol. 2. Philadelphia: WB Saunders. 2000:1597-1603. Chapter 35

Siegler R.L. The hemolytic uremic syndrome. Pediatr Clin N Am. 1995;42(6):1505-1522.

Stewart C.L., Tina L.U. Hemolytic uremic syndrome. Pediatr Rev. 1993;14(6):218-224.

Tarr P.I., Gordon C.A., Chandler W.L. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005;365(9464):1073-1086.

Trachtman H., Christen E. Pathogenesis, treatment and therapeutic trials in hemolytic uremic syndrome. Curr Opin Pediatr. 1999;11:162-168.

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