Definition of Hemolytic-Uremic Syndrome
Hemolytic-Uremic Syndrome (HUS) is defined as a complication syndrome related to the infection with shiga-toxin producing E. coli that is characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenia and progressive acute renal failure.
Epidemiology of Hemolytic-Uremic Syndrome
HUS has an incidence of approximately 2 per 100,000 per year in the United States. The condition is more common among young children with a peak incidence of about 6 per 100,000. HUS has also been reported without previous history of infection with shiga-toxin producing E. coli. The incidence of this atypical form of HUS is estimated to be around 2 per 100,000 per year.
HUS is more common among African Americans. Males and females are affected equally without any significant gender preference. While the condition is more common in young children, adults can also develop HUS and usually with long-term morbidity.
While acute renal failure is common in HUS, 85% of the affected individuals regain normal renal function eventually. HUS is also associated with hypertension, which can lead to other morbidities including stroke, seizures and bleeding complications because of the thrombocytopenia.
Etiology of Hemolytic-Uremic Syndrome
Hemolytic uremic syndrome mostly affects children during epidemics and present after a prodrome of diarrhea. The causative organisms during these epidemics include:
Bacterial causes :
- The most common etiology of HUS cases is related to shiga-toxin producing E. coli dysentery.
- Salmonella typhi.
- Campylobacter jejuni.
- Mycoplasma species.
- S. dysentriae.
- Campylobacter jejuni
Viral causes :
- Aspergillus fumigatus.
- Influenza triple-antigen vaccine.
- Typhoid-Para typhi A and B.
- Polio vaccine.
Secondary/ sporadic Hemolytic uremic syndrome is associated with :
- Pregnancy especially if the patient develops preeclampsia.
- Patients usually develop hemolysis, elevated liver enzymes and low platelets (HELLP syndrome)
- Drugs such as Mitomycin, cisplatin, cyclosporine, Clopidogrel and quinines have been associated with non-infectious HUS.
- Cancers such as mucin producing adenocarcinomas.
- Shiga toxin-producing E. coli (STEC)
- E. coli O157:H7
- Incidence: 5 – 10% infected
- E. coli (non-O157)
- Cause same spectrum of disease
- Shiga toxin 2 most important
- E. coli O157:H7
- Shigella dysenteriae
Pathophysiology of Hemolytic-Uremic Syndrome
The most important pathogenic step in the pathophysiology of HUS is the formation of microthrombi within the arterioles and capillaries. This is the result of endothelial cells injury. When red blood cells become entrapped within these microscopic thrombi, they are fragmented and hemolysis ensues.
The most common cause of HUS is O157:H7 E. coli, which is a strain of E. coli that produces a shiga-like toxin. This type of E. coli is usually more pathogenic and invasive than non-shiga-toxin producing E. coli. As a consequence, approximately 75% of the infected patients develop acute kidney failure.
In addition to that, endothelial cell injury is also evident in patients infected by shiga-toxin producing E. coli, which triggers the formation of microscopic thrombi, which are responsible for the non-immune hemolysis.
Clinical Presentation of Hemolytic-Uremic Syndrome
Patients with HUS usually have a recent history of gastroenteritis and diarrheal disease 2 days up to one week before the onset of renal failure. Infants and young children become irritable or lethargic.
Seizures are common in patients affected by HUS. Other neurologic symptoms are also common due to hypertension and the microthrombotic phenomenon. Half of the cases develop anuria.
Physical examination reveals hypertension in half of the cases. Adults affected with HUS usually develop severe hypertension and subsequent neurological sequelae. Edema due to acute renal failure is commonly identified in more than two thirds of the cases.
Because patients become anemic, they can develop severe pallor. Bleeding complications are also common because of the thrombocytopenia and the consumption of the thrombotic factors by the formation of microthrombi.
Diagnostic Workup for Hemolytic-Uremic Syndrome
Laboratory investigations are helpful in the evaluation of the HUS patient. Urine analysis confirms acute renal injury as proteinuria and hematuria are common.
Blood urea nitrogen and serum creatinine levels are usually elevated due to acute renal injury. Patients can also have serum electrolyte disturbances. A complete blood count reveals severe anemia, along with thrombocytopenia.
Thrombocytopenia severity is usually variable and is considered as a good indicator of disease severity. Because of the formation of microthrombi, consumptive coagulopathy is common and examination of activated partial thromboplastin time, fibrinogen degradation product and D-dimer levels is indicated.
Patients with HUS have non-immunologic hemolytic anemia; therefore, Coombs test is negative. Serum bilirubin and lactate dehydrogenase levels are usually elevated.
Stool culture is also useful in the evaluation of the HUS patient because it can help identify the presence of O157:H7 E. coli or Shigella, both of which are commonly associated with HUS.
Differentiation from classic thrombotic thrombocytopenic purpura can be made by determining the levels of ADAMTS-13. Patients with thrombotic thrombocytopenic purpura usually have severely diminished the activity of this enzyme, while patients with HUS have normal or slightly deficient activity.
When in doubt, a renal biopsy might be performed to confirm the diagnosis. This is rarely needed in children, but might be indicated in adults. If performed, patients with HUS have small occlusive lesions of the arterioles within the kidneys. In contrast to classical thrombotic thrombocytopenic purpura, patients with HUS usually have a disease that is confined to the kidneys.
Treatment of Hemolytic-Uremic Syndrome
Patients with HUS should receive mainly supportive therapy rather than specific treatment. Certain antibiotics, such as ciprofloxacin, should be avoided when treating shiga-toxin producing E. coli because they are known to increase the production of the shiga toxin, hence increase the risk of the development of HUS.
Supportive treatment includes adequate blood pressure control. Patients who develop seizures or other neurologic signs should receive prophylactic phenytoin. Fluid replacement therapy and electrolytes balance correction is more important in the management of HUS than the prescription of antibiotics.
Plasma exchange transfusion is an old method of management but still applied in desperate situations where other options are unavailable. It is effective especially in cases of atypical HUS.
Eculizumab can also be used in patients with atypical HUS to prevent further damage to healthy cells. However, the drug is less effective than plasma exchange. Plasma exchange for non-shiga-toxin HUS has changed this condition from a potentially fatal disease to a curable disease!
Patients with end-stage renal failure due to shiga-toxin producing E. coli are possible candidates for renal transplantation. On the other hand, patients with atypical HUS that is not related to E. coli should not receive kidney transplantation because the recurrence rate of kidney injury in the transplanted kidney is very high.
Patients who develop acute kidney failure due to HUS should have a protein-limited diet. Early limiting of protein intake has been found to be associated with a more favorable outcome.