Hemolytic uremic syndrome

1. W. P. Rivindu H. Wickramanayake
Group no. 04a
6th Year 2nd Semester – 2020 September
Tbilisi State Medical University, Georgia
Hemolytic Uremic Syndrome

2. ● HUS is thrombotic microangiopathy characterized by the presence of the
triad of symptoms: thrombocytopenia, acute renal impairment, and
microangiopathic hemolytic anemia.
● Thrombotic microangiopathy is the formation of platelet microthrombi in
walls of small blood vessels (arterioles and capillaries), causing platelet
consumption leading to thrombocytopenia, nonimmune hemolytic anemia
(Coombs negative), and acute renal injury.
● Although traditionally thought as a triad, HUS presentation may vary
based on different etiology.
● HUS can be a life-threatening condition requiring prompt diagnosis and
treatment.
● One of the leading causes of acute renal injury in the pediatric population.
Introduction

3. ● HUS has two variants termed typical and atypical HUS.
● The typical variant is caused by Shiga-like toxin (verotoxin) produced
by E. coli (O157: H7) and Shiga toxin by Shigella dysenteriae.
● The atypical form is linked to bacteria, medication, or immune
processes capable of endothelial damage.
● Streptococcus pneumoniae is a common bacterial infection associated
with atypical HUS, while other causes include
Mycoplasma pneumoniae, Clostridium difficile, HIV, histoplasmosis,
and coxsackievirus and H1N1 Influenza A.
● Common drugs associated with HUS include mitomycin C,
cyclosporine, cisplatin, cocaine, quinine, and rarely FK506 (tacrolimus)
and interferon-alpha.
Etiology

4. ● Most often associated with children under ten years old, with
the majority occurring in those less than 5 years old.
● More than 90% of the typical HUS is caused by Shiga toxin-
producing Escherichia coli (STEC).
● The yearly incidence of typical HUS is 3 cases per 100,000.
● Atypical HUS occurs more sporadically with an estimated
incidence of 10 cases per 1,000,000.
● About 40% of the atypical HUS is associated with S.
pneumoniae.
● The estimated fatality rate for both atypical and typical HUS is
less than 5%.
Epidemiology

5. ● Typically associated with bacterial infection resulting from the consumption of undercooked
beef or unpasteurized milk.
● The Shiga toxin formed by the E. coli in typical HUS is then absorbed by the villi in the
intestines, allowing the toxin to enter the bloodstream.
● The toxin then binds to glycosphingolipid found on multiple different cells throughout the
body. The damage that ensues leads to an increase in thrombin and fibrin levels resulting in
microthrombi being laid down.
● These microthrombi lead to platelet consumption, causing thrombocytopenia.
● Microthrombi present in the blood vessel also leads to the mechanical breakdown of red blood
cells, causing hemolytic anemia.
● As the red blood cells are hemolyzed, there is a further increase in platelet use, causing
thrombocytopenia.
● The Shiga toxin has a high affinity for globotriaosylceramide (Gb3) membrane receptor present
in glomerular endothelium & tubular cells, causing widespread damage resulting in glomerular
necrosis, cellular apoptosis & microangiopathic thrombosis leading to acute renal injury.
Pathophysiology

6. Continued;
● Atypical HUS is a broad term used for those patients who develop HUS not
associated with a Shiga-toxin illness.
● A common etiology is associated with S. pneumoniae that produces a
neuraminidase enzyme.
● This enzyme targets N-acetylneuraminic acid found on the surface of red blood
cells.
● When the enzyme cleaves N-acetylneuraminic acid, a T antigen is exposed,
initiating an immune response.
● Another proposed mechanism includes increased expression and binding of
pneumococcal surface proteins (Tuf and PspC) with human plasminogen leading
to bacterial surface plasmin activation and widespread endothelial damage
exposing subendothelial matrix and subsequent thrombotic microangiopathy.
● HIV, Mycoplasma pneumoniae, histoplasmosis, and coxsackievirus have also
been linked to atypical HUS.

7. Continued;
● Another form of atypical HUS is called atypical familial HUS.
● In short, this disease results from a change in the genetic makeup
for part of the complement pathway resulting in unregulated
endothelial damage.
● As research continues, multiple different genetic mutations have
been linked to atypical HUS.
● These patients are at higher risk for recurrent episodes of atypical
HUS.
● A rare form of HUS associated with pregnancy and postpartum is
linked to widespread complement activation triggered by
pregnancy, and thus patients benefit from eculizumab (anti-C5
humanized monoclonal antibody).

8. ● Of the kidney shows fibrin deposition in the capillary lumen with
extensive necrosis of the renal cortex and widespread renal arterial
thrombosis.
● Glomerular mesangial expansion and endothelial proliferation are part
of early histological changes while proliferation and aneurysmal
dilatation of hilar arterioles with the double contour of the basement
of the glomeruli are part of the late changes.
● Immunofluorescence demonstrates glomerular IgM, C3, and C1q
deposition.
● Electron microscopy shows swollen mesangium with intraluminal
platelet microthrombi and subendothelial space widening filled with
fibrinogen.
● Obliterating endarteritis may be seen later.
Histopathology

9. ● Is most often associated with a gastrointestinal illness; thus, patients
presenting early in the course of the disease will complain of fever,
abdominal pain, nausea, vomiting, and diarrhea.
● Diarrhea is often bloody and is within 3 days of diarrhea onset.
Bloody diarrhea that ensues can be secondary to colitis from the
invasion of the gastrointestinal cells or ischemia related to a vascular
lesion.
● After a week of such gastrointestinal symptoms, patients may start
to develop symptoms more closely related to the triad that defines HUS:
specifically, symptoms related to anemia (syncope, shortness of
breath, and jaundice) and kidney impairment (oliguria/anuria,
hematuria).
● The skin exam may show small ecchymosis and mucosal bleeding.
History and Physical

10. ● Late in the course of the infection, patients may develop seizures and
encephalopathy related to ongoing uremia and other electrolyte
derangements.
● In rare cases, the colitis can be severe enough to cause intestinal necrosis and
perforation.
● In atypical HUS, a gastrointestinal illness is not usually the initial insult, and
a thorough history and physical is required to find the offending agent.
● If S. pneumoniae is the source, the patient may site a recent respiratory
illness.
● A review of any new medications or chronic autoimmune diseases is
necessary.
● These patients typically have decreased urine output, pallor, and scattered
ecchymosis.
Continued;

11. ● The diagnosis requires a high index of suspicion based on symptoms, travel
history, and dietary history.
● A complete blood count (CBC), comprehensive metabolic panel (CMP), and a
urinalysis may aid in the diagnosis.
● The CBC shows both anemia and thrombocytopenia.
● Hemoglobin is often less than 10 g/dl.
● A peripheral smear reveals characteristic schistocytes.
● The Coombs test is negative, consistent with mechanical hemolysis.
● The CMP reveals elevated creatinine consistent with acute kidney injury.
● It also shows signs of acute hemolysis with elevated indirect bilirubin and
elevated lactate dehydrogenase.
● As the disease progresses, hyponatremia and hyperkalemia may develop as
the patient enters into renal failure.
● Urinalysis reveals hematuria and proteinuria.
Evaluation

12. ● Begins with good supportive care. The patients are often fluid depleted and thus benefit from
several fluid boluses.
● A careful assessment of the patient’s overall kidney function so as to avoid giving too much
fluid in the setting of kidney failure. A subset of patients will go on to develop oliguric renal
failure (<0.5 ml/kg/hr x72 hr) and require dialysis.
● Most experts do not recommend antibiotics and antiperistaltic agents to treat diarrheal illness.
They believe that this will increase the complications associated with the E. coli infection.
● Patients should have their anemia corrected with packed RBCs when hemoglobin reaches 7
to 8 g/dl or hematocrit less than 18%.
● The treatment of thrombocytopenia is often unnecessary, given the continued consumption
during the disease.
● Furthermore, there is concern that platelet transfusion leads to worsening thrombosis.
Exceptions to this are those with active bleeding or before a medical procedure.
● Patients diagnosed with HUS should be admitted to the hospital for further monitoring.
● Those with encephalopathy or need for dialysis should be admitted to an intensive care unit.
● Familial atypical HUS requires consultation with hematology for possible plasmapheresis.
Treatment / Management

13. ● Conditions that may present with hemolytic anemia,
thrombocytopenia, & acute kidney injury
1) Thrombotic thrombocytopenic purpura (TTP):
- TTP is thrombotic microangiopathy characterized
by a pentad of hemolytic anemia, thrombocytopenia, renal
dysfunction, fever, and neurological dysfunction.
- It is due to deficiency or mutation in "a disintegrin
and metalloproteinase with a thrombospondin type 1 motif member
13" (ADAMTS13) and usually has the adult-onset of symptoms.
Differential Diagnosis

14. 2) Disseminated intravascular coagulation (DIC):
- DIC is the systemic activation of the coagulation
cascade and is characterized by abnormal coagulation studies,
including prolonged prothrombin time and activated partial
thromboplastin time and elevated D dimer and fibrin degradation
products which are usually normal in HUS.
- Patient with DIC usually has a very serious
underlying illness like septic shock, trauma, malignancy, etc.
Continued;

15. 3) HELLP syndrome:
- It is characterized by hemolysis of red blood
cells, elevated liver enzymes, and low platelet count occurring in
pregnancy and severe preeclampsia.
4) Systemic vasculitis:
- These patients typically present with
inflammatory signs like fever, rash, and arthralgia and lack
prodromal diarrhea.
Continued;

16. ● The long-term complication rate from typical HUS is low, and most patients
make a full recovery. Yearly evaluation for proteinuria, raised blood pressure,
and renal insufficiency should be done for at least 5 years.
● Those patients who require dialysis have the highest risk of long-term chronic
kidney disease.
● Patients who develop significant colitis, as evidenced by fever, leukocytosis,
and severe abdominal pain, are at a higher risk of developing abdominal
strictures.
● Those diagnosed with familial atypical HUS are at the highest risk of
developing end-stage renal disease (ESRD) requiring routine dialysis.
● Familial atypical HUS patients also require several rounds of plasma exchange,
placing the patient at risk for line infections.
● Other rare complications include transient or permanent diabetes mellitus,
seizures, coma, stroke, abnormal liver functions, and hepatomegaly.
Complications

17. ● Typically depends on the prompt initiation of treatment.
● Acute complications like acute renal injury, coma, and death, as well
as progression to chronic renal failure, can be prevented with timely
intervention.
● Overall mortality from HUS is less than 5%, while long term renal
complications occur in 5% to 25% of the children with HUS.
Prognosis
1. https://www.ncbi.nlm.nih.gov/books/NBK556038/
2. Noris M, Remuzzi G. Hemolytic uremic syndrome. J. Am. Soc. Nephrol. 2005 Apr;16(4):1035-50. [PubMed]
3. Golubovic E, Miljkovic P, Zivic S, Jovancic D, Kostic G. Hemolytic uremic syndrome associated with novel
influenza A H1N1 infection. Pediatr. Nephrol. 2011 Jan;26(1):149-50. [PubMed]
4. Fitzpatrick MM, Shah V, Trompeter RS, Dillon MJ, Barratt TM. Long term renal outcome of childhood haemolytic
uraemic syndrome. BMJ. 1991 Aug 31;303(6801):489-92. [PMC free article] [PubMed]
References