Atypical hemolytic uremic syndrome (aHUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure, primarily resulting from complement system abnormalities or infections. Treatment options include eculizumab, which is FDA-approved for aHUS, and other therapies like therapeutic plasma exchange, although the latter's efficacy is unproven in controlled trials. Prognosis varies based on genetic mutations associated with the disease, significantly impacting the risk of recurrence post-renal transplantation.

1. DISCUSSION
ATYPICAL HEMOLYTIC UREMIC
SYNDROME

2. • Hemolytic-uremic syndrome consists of the
triad of microangiopathic hemolytic anemia,
thrombocytopenia, and acute renal failure.
• It is the most common cause of acute renal
failure in the pediatric population.
• The clinical course of hemolytic-uremic
syndrome can vary from subclinical to life
threatening.

3. • Studies have revealed distinct subgroups of
hemolytic-uremic syndrome and have
identified several etiologies for the disease.
• STEC-HUS is used to describe hemolytic-
uremic syndrome mediated by Shiga toxin
(Stx)–producing Escherichia coli. This is also
called classic, typical, Stx, diarrhea-positive, or
D + hemolytic-uremic syndrome.

4. • Pneumococcal-associated HUS is a subtype of
atypical hemolytic-uremic syndrome,
mediated by neuraminidase in the presence of
infection withStreptococcus pneumoniae.
• This is also called neuraminidase-associated
hemolytic-uremic syndrome.

5. ATYPICAL HEMOLYTIC UREMIC
SYNDROME
• Atypical HUS (aHUS) is used to describe
hemolytic-uremic syndrome not mediated by
Shiga toxin.
• This is also called diarrhea-negative, non–
diarrhea-associated, or D - hemolytic-uremic
syndrome.
• This disease is usually mediated by
abnormalities of the complement system or
other heritable factors.

6. CAUSES
• Causes of aHUS include the following:
• Inherited (eg, mutations in the gene for factor
H, a complement regulatory protein)
• S pneumoniae (neuraminidase-associated)
• Portillo virus
• Coxsackie virus
• Influenza virus
• Epstein-Barr virus

7. Drugs (eg, chemotherapy, cyclosporine)
• Bone marrow or hematopoietic stem cell
transplantation
• Malignancy
• Idiopathic
• Systemic lupus erythematosus (SLE)
• Glomerulonephritis, especially
membranoproliferative glomerulonephritis

8. SIGN AND SYMPTOMS
• Clinical signs and symptoms of aHUS can
include abdominal pain, confusion, fatigue,
edema (swelling), nausea/vomiting and
diarrhea.
• aHUS often presents with malaise and
fatigue, as well as microangiopathic anemia.
• However, severe abdominal pain and bloody
diarrhea are unusual.

9. LABORATORY FINDINGS
• Classic findings in hemolytic-uremic syndrome
(HUS) include anemia and thrombocytopenia,
with fragmented RBCs (eg, schistocytes,
helmet cells, burr cells).
• Testing for ADAMTS13 activity may help
distinguish between atypical hemolytic-uremic
syndrome (aHUS) and thrombotic
thrombocytopenic purpura (TTP).

10. • WBC differential may reveal a left shift (ie,
immature WBCs, including bands, myelocytes,
metamyelocytes)
• Coombs test results are negative, except
with S pneumoniae –associated hemolytic-
uremic syndrome.
• Reticulocyte count is elevated.
• levels of serum haptoglobin, which binds
hemoglobin, are decreased.

11. • Prothrombin time (PT) and activated partial
thromboplastin time (aPTT) are normal.
• Fibrin degradation products are increased.
• Fibrinogen levels are increased or within
reference range.
• BUN and creatinine levels are elevated.

12. • Various electrolyte and ion derangements may
be present because of vomiting, diarrhea,
dehydration, and renal failure; these may
include hyponatremia, hyperkalemia,
hyperphosphatemia, hypocalcemia, and
acidosis.
• Phosphorusconcentration is elevated.
• Patients with hyperkalemia may require ECG
monitoring

13. IMAGING STUDIES
• Consider performing chest radiography to
evaluate for pulmonary congestion or edema,
if clinically indicated.
• Renal ultrasound typically reveals nonspecific
findings (eg, increased echogenicity) and is of
little use. Ultrasonography may be helpful if
the diagnosis is uncertain or if one needs
evaluation of blood flow in the large renal
vessels.

14. • Abdominal ultrasonography or CT scanning
may help if clinical findings raise suspicion of
intestinal obstruction or perforation.
• Noncontrast CT scanning or MRI of the head is
indicated in patients with CNS symptoms or
acute mental status changes.
• Avoid iodinated contrast or gadolinium in
patients with decreased renal function.

15. HISTOLOGICAL FINDINGS
• Renal biopsy is not usually necessary for
diagnosis and may be contraindicated due to
thrombocytopenia.
• Histologic analysis of kidney specimens reveals
thrombotic microangiopathy, with swollen
glomerular endothelial cells and red cells and
platelets in the capillaries.

16. • Accumulation of fibrinlike material in the
subendothelial space creates a thickened
appearance to the capillary walls.
• Thrombi may be observed in the glomerular
capillaries and arterioles. These findings can
progress to acute cortical necrosis involving
both glomeruli and convoluted tubules.

17. • Tissue section of the gut shows
microangiopathy, with endothelial cell injury,
and thrombosis, with submucosal edema and
hemorrhage.
• Microthrombi may be observed in other
organs, including the lungs, liver, heart,
adrenal glands, brain, thyroid, pancreas,
thymus, lymph nodes, and ovaries.

18. FLUID THERAPY
• Use potassium-free fluids until renal function
has stabilized. Mild hypokalemia is tolerable
and much less critical than hyperkalemia.
Treat severe or symptomatic hypokalemia
with very cautious potassium replacement.
• Once fluid deficits have been replaced, restrict
fluid replacement to insensible losses plus
actual output.

19. • Monitor hydration status closely and
frequently. This includes serial and frequent
measurements of body weight, fluid intake
and output, heart rate, and blood pressure.
• Patients may develop fluid overload or
hyperkalemia if not carefully managed.

20. • Management of aHUS is very difficult and
remains incompletely understood.
• Clinicians caring for patients with aHUS
should search recent literature and confer
with physicians with expertise in this disorder.
• Discontinue the offending agent if a drug-
associated cause is identified.

21. • Treat bacterial infections (eg, S pneumoniae)
promptly and aggressively.
• Prior to the development of eculizumab,
plasma therapies formed the mainstay of
treatment for most forms of aHUS.
• These therapies use donor plasma products
to replace the deficient or abnormal von
Willebrand factor (vWF) metalloproteinase or
complement factors.

22. THERAPEUTIC PLASMA EXCHANGE
• Therapeutic plasma exchange (TPE), which is
also called plasmapheresis, was previously the
preferred plasma therapy for aHUS, although
its efficacy was never confirmed in controlled
clinical trials.
• TPE removes the patient's plasma and
replaces it with fresh frozen plasma (FFP) or a
similar product.

23. • Albumin should not be used for replacement
because it does not contain the vWF
metalloproteinase or complement factors,
except in the case of pneumococcal-
associated hemolytic-uremic syndrome or
neuraminidase mediated hemolytic-uremic
syndrome .

24. • The role of plasma therapy in pneumococcal-
associated hemolytic-uremic syndrome is
controversial.
• Donor plasma may contain antibodies to the
T antigen, which, in theory, could worsen the
hemolytic process.
• Alternately, plasma exchange may remove
neuraminidase and decrease the amount of
circulating anti–T antibody.

25. PLASMA INFUSION
• Plasma infusion consists of simply infusing
donor plasma, such as FFP or cryoprecipitate-
reduced plasma.
• this delivers the absent or abnormal vWF
metalloproteinase or complement factors.
• Plasma infusion does not remove the
abnormal factors, as TPE does.

26. • The sole advantage of plasma infusion over
TPE is its simplicity, because it can be
performed in almost any medical facility and
does not require specialized equipment,
central venous access, or specially trained
staff.
• Studies comparing TPE to plasma infusion
have found superior outcomes with TPE.

27. ECULIZUMAB
• Eculizumab (Soliris) is the only treatment
approved by the US Food and Drug
Administration (FDA) (September, 2011) for
adults and children with aHUS.
• Approval was based on data from adults and
children who were resistant or intolerant to,
or receiving, long-term plasma
exchange/infusion.

28. • Data also included children (aged 2 mo to 17
y) who received eculizumab with or without
prior plasma exchange/infusion.
• Eculizumab demonstrated significant
improvement in platelet count from baseline
(P = .0001).
• Thrombotic microangiopathy events were
reduced, and maintained or improved kidney
function was also reported.

29. • Eculizumab is a humanized monoclonal
antibody against C5, inhibiting progression of
the complement cascade and blocking
terminal complement activation.
• Specifically, eculizumab prevents cleavage of
C5 into C5a and C5b, the latter being an
essential component of the membrane attack
complex.

30. • Eculizumab is the treatment of choice for patients
with aHUS. Its advantages over plasma exchange
include the following:
• Efficacy proven in controlled clinical trials
• FDA approval for indication of aHUS
• Simple intravenous administration
• No requirement for specialized equipment and
specially trained personnel
• No need for donor plasma products

31. • Eculizumab therapy should be started
immediately upon diagnosis of aHUS.
• Treatment is given weekly initially and then
tapered to every 2 weeks (except for patients
weighing < 10 kg, who receive it every 3 wk).
• Eculizumab may be used in place of plasma
exchange. If patients are receiving concomitant
plasma exchange, supplemental eculizumab
dosing should be given after plasma exchange.

32. • Inhibition of complement activation increases
susceptibility to infection, especially with
encapsulated organisms.
• Patients should receive vaccine for Neisseria
meningitidis immediately prior to eculizumab
treatment if they have not been immunized or if
their immunization status is unknown.
• Patients should receive antibiotic prophylaxis
for N meningitidis for at least 2 weeks following
vaccination to allow time for development of
immunity.

33. • The optimal duration of eculizumab therapy is
unknown and may be life-long.
• No clear data or guidelines exist to determine
criteria for discontinuance.
• If treatment is discontinued, patients should
be monitored carefully for signs of relapse.

34. RENAL TRANSPLANTATION
• Renal transplantation in patients with aHUS is
more difficult because of the high risk of
recurrence and allograft loss.
• The risk of recurrence varies with the
complement mutation identified; such testing
is essential, as is planning and counselling
patients about transplantation options.

35. • Note the following mutations and recurrence
rates
• Factor H mutation: 80-100% recurrence
• Factor I mutation: 80% recurrence
• Membrane cofactor protein mutation: 10-20%
recurrence
• No (known) mutation identified: 30%
recurrence

36. OTHER MEDICATION
• Corticosteroids may be of value in aHUS if the
patient has an autoimmune-produced inhibitor of
ADAMTS13. Clinical testing for inhibitors is
available but has a long turnaround time.
• Limited case reports describe using intravenous
immune globulin (IVIG) in patients with aHUS
associated with organ transplantation. IVIG does
not have a role in hereditary aHUS nor in STEC-
HUS.

37. COMPLICATIONS
• Renal system complications are as follows:
• Renal insufficiency
• Renal failure
• Hypertension

38. • CNS complications are as follows:
• Mental retardation
• Seizures
• Focal motor deficit
• Optic atrophy
• Cortical blindness
• Learning disability

39. • Endocrine system complications are as
follows:
• Diabetes mellitus
• Pancreatic exocrine insufficiency

40. • GI system complications can include intestinal
necrosis.
• Cardiac system complications can include
congestive heart failure.

41. PROGNOSIS
• Patients with aHUS are at risk for relapses and
a higher risk of progression to end-stage renal
disease (ESRD).
• Ongoing treatment with eculizumab reduces
this risk.

42. PATIENT EDUCATION
• Diet concerns are as follows:
• Low-salt diet to decrease risk of hypertension
• Diet high in iron and folic acid content to help
recover from anemia
• High-energy diet to help patient regain lost
weight
• Social worker or psychologist consultation can
help the family cope with the illness.

43. REFERENCES
• http://emedicine.medscape.com/article/9820
25-followup#e7
• http://ghr.nlm.nih.gov/condition/atypical-
hemolytic-uremic-syndrome
• https://en.wikipedia.org/wiki/Atypical_hemol
ytic_uremic_syndrome
• https://rarediseases.org/rare-
diseases/atypical-hemolytic-uremic-
syndrome/