HEMOLYTIC-UREMIC SYNDROME

Dr. Avinash Jha (DNB Paediatrics)

Batra Hospital,New Delhi
 HEMOLYTIC-UREMIC SYNDROME
• common cause of community-acquired acute
kidney injury in young children
• the most common form of thrombotic
microangiopathy (TMA) in children
• the most common cause of children receiving acute
dialysis
• characterized by the triad of
- microangiopathic hemolytic anemia
- thrombocytopenia
- acute renal insufficiency
 Classification

HUS

Diarrheal Atypical SECONDARY

-STEC-HUS Drug induced

-Non STEC (shigella dysenteriae type 1)
- Neuraminidase producing S.pneumoniae Complement pathway factors deficiencies Post Transplantation
Malignancy
HIV infection
 Current classification of HUS and TMAs
• DIARRHEA-ASSOCIATED HUS DRUG INDUCED
• STEC (Escherichia coli O157:H7) • Cyclosporine
• STEC (E.coli 0121 and 0104:H4) • Tacrolimus
• Non-STEC (Shigella dysenteriae type 1) • Mithramycin
• HUS SECONDARY TO SYSTEMIC INFECTIONS • Quinine
• Neuraminidase (Streptococcus pneumoniae) • Cocaine
• Human immunodeficiency virus • Anti–vascular endothelial
• Influenza growth factor therapy
• Human herpes virus 6 SYSTEMIC DISEASE ASSOCIATED
• Parvovirus B19 • Systemic lupus erythematosus
• Malaria • Coexisting nephropathies
• ATYPICAL HUS DUE TO COMPLEMENT DYSREGULATION • Malignant hypertension
• Factor H deficiency (mutations, autoantibodies) • Malignancies
• Factor I deficiency (mutations) • Cobalamin C defect
• Factor B (gain-of-function mutations)
• Diacylglycerol kinase epsilon
• Membrane cofactor (MCP) deficiency (mutations)
mutation
• C3 deficiency (mutations, autoantibodies)
TRANSPLANT ASSOCIATED
• Thrombomodulin deficiency (mutations)
• Anti–complement factor H antibody
• Stem cell transplant
• Unknown • Bone marrow transplant
• THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) • Renal
• Inherited ADAMTS13 deficiency (mutations)
• Heart
• Intestinal
 STEC HUS
• The most common form of HUS is caused by Shiga toxin–
producing Escherichia coli (STEC), which causes
prodromal acute enteritis and is commonly termed STEC-
HUS or diarrhea-associated HUS
• STEC-HUS accounts for about 90% of all HUS cases in
childhood
• In Asia and in southern Africa, the toxin of Shigella
dysenteriae type 1 is causative
• In Western countries, verotoxin or Shiga toxin–producing
E. coli (STEC) is the usual cause
• O157:H7 is most common in Europe and the Americas
• A large epidemic of HUS in Europe was caused by Shiga
toxin–producing E. coli O104:H4
 Transmission of infection
• The reservoir of STEC is the intestinal tract of domestic animals,
usually cows
• transmitted by
- undercooked meat
- unpasteurized (raw) milk
- apple cider
- contaminated hamburger or
other foods cross-contaminated
- contaminated municipal water supplies
- swimming in contaminated ponds
lakes, or pools
Pathogenesis – Diarrhea associated HUS
Pathogenesis – Pneumococcal associated HUS
Neuraminidase cleaves sialic acid on membranes of endothelial
cells , red cells, and platelets

Exposes underlying cryptic Thomsen-Friedenreich (T)

antigen

Endogenous immunoglobulin M (IgM) antibodies recognize and react with T

antigen to trigger hemolysis and anemia with a positive direct Coombs test
Pathogenesis – Inherited forms of HUS
Inherited deficencies of ADAMTS13 & regulators of the
complement cascade

Predispose patients to developing HUS but do not cause the

disease per se

HUS is often triggered by an inciting event such as an

infectious disease
Pathogenesis – Inherited forms of HUS
• The absence of ADAMTS13 impairs cleavage of
von Willebrand factor multimers, which
enhances platelet aggregation.
• Factor H plays a central role in complement
regulation, primarily arresting the amplification
and propagation of complement activation
• Mild endothelial injury that would normally
resolve instead evolves to an aggressive
microangiopathy because of the inherited
deficiencies of these factors.
 Pathology in Kidney
• Early glomerular changes include:
-thickening of the capillary walls caused by swelling of
endothelial cells and
-accumulation of fibrillar material between endothelial cells
and the underlying basement membrane, causing narrowing of
the capillary lumens.
• Platelet–fibrin thrombi are often seen in glomerular capillaries.
• Thrombi are also seen in afferent arterioles and small arteries
with fibrinoid necrosis of the arterial wall, leading to renal
cortical necrosis from vascular occlusion.
• Late findings include glomerular sclerosis and obsolescence
secondary to either severe direct glomerular involvement or
glomerular ischemia from arteriolar involvement
Thrombotic Microangiopathy
 Atypical HUS
• Genetic forms of HUS (atypical, nondiarrheal) compose the second
major category of the disease
• Inherited deficiencies of either von Willebrand factor–cleaving
protease (ADAMTS13) or complement factor H, I, or B can cause HUS
• Some of these may be due to cobalamin C mutations
• A major feature characteristic of genetic forms of HUS is the absence
of a preceding diarrheal prodrome
• Genetic forms of HUS can be indolent and unremitting once they
become manifest, or they can have a relapsing pattern precipitated
by an infectious illness
• HUS can be superimposed on any disease associated with
microvascular injury, including malignant hypertension, systemic
lupus erythematosus, and antiphospholipid syndrome or drug
induced
 Clinical Presentation
• Diarrheal Form:
- m/c in Preschool and school age children
-onset of HUS – 5 to 7 days after the onset of
gastroenteritis with fever,vomiting,abdominal pain,
and diarrhea.
-diarrhea is often bloody, but not necessarily so
- Sudden onset of Pallor,weakness,and lethargy
heralds the onset of HUS
- Oliguria +/- , Can present with dehydration or
volume overload
 Clinical Presentation
• Pneumococci associated HUS:
-usually quite ill with pneumonia,
empyema,and bacteremia
• Genetic forms of HUS:
-Insidious in onset,triggered by variety of
illnesses
Note: Disease can progress from mild to severe
form leading to multisystem involvement and
complications very rapidly
 Complications
• Volume overload/ dehydration
• Hyperkalemia
• Renal insuffiency
• Hypertension
• Severe anemia
• Irritability/Seizure / Encephalopathy features
• Arrhythmia/Pericarditis/Myocardial
dysfunction
 Diagnosis
• The diagnosis is made by the combination of microangiopathic
hemolytic anemia with schistocytes, thrombocytopenia (usually
20,000-100,000/mm3), and some degree of kidney involvement
• The Coombs test is negative, with the exception of pneumococci-
induced HUS, where the Coombs test is usually positive.
• Leukocytosis present
• Urinalysis - microscopic hematuria and low-grade proteinuria
• Renal insufficiency - from mild elevations in serum blood urea
nitrogen and creatinine to acute,anuric kidney failure.
• Stool culture +/- for STEC-HUS, Often negative, ask for h/o
diarrheal prodrome
• If no history of diarrheal prodrome or pneumococcal infection is
obtained, then evaluation for genetic forms of HUS should be
considered
 Differential diagnosis

• Other causes of acute kidney injury associated

with a microangiopathic hemolytic anemia and
thrombocytopenia should be considered and
excluded, such as :
- systemic lupus erythematosus
- malignant hypertension
- bilateral renal vein thrombosis
• A kidney biopsy is rarely indicated to diagnose
HUS
 Treatment
• With early recognition and intensive supportive care, the mortality rate for
diarrhea-associated HUS is < 5%
• 50% require dialysis support during the acute phase of the disease
• Approach:
- early recognition of disease
- monitoring for potential complications
- Supportive care
• Supportive care includes :
-careful management of fluid and electrolytes
-prompt correction of a volume deficit,
-control of hypertension, and
-early institution of dialysis if the patient becomes significantly
oliguric or anuric, particularly with hyperkalemia
• Red cell transfusions (in severe acute hemolysis).But In pneumococci-associated
HUS, it is critical that any administered red cells be washed before transfusion to
remove residual plasma, because endogenous IgM directed against the revealed T
antigen can play a role in accelerating the pathogenesis of the disease
 Should we?

• Low Platelet count – Should we give Platelets?

• Thrombi are formed – Should we give

Anticoagulant/Fibrinolytic/Antiplatelet?

• Infection related HUS- Should we give antibiotics?

 Answer

• Should we give Platelets?

- Platelets should generally not be
administered, regardless of the platelet count,
to patients with HUS because they are rapidly
consumed by the active coagulation and
theoretically can worsen the clinical course.
- Despite low platelet counts, serious bleeding
is very rare in patients with HUS
 Answer
• Should we give Anticoagulant/Fibrinolytic/Antiplatelet?
- contraindicated because they increase the risk of
serious hemorrhage

• Should we give antibiotics?

- Antibiotic therapy to clear enteric toxigenic organisms
(STEC) can result in increased toxin release, potentially
exacerbating the disease, and therefore is not
recommended.
- However, prompt treatment of causative
pneumococcal infection is important
 Plasma infusion/Plasmapheresis
• It has been proposed for patients suffering severe
manifestations of HUS with serious CNS involvement
• It is specifically contraindicated in those with
pneumococcal-associated HUS because it could
exacerbate the disease
• Plasma therapy can be of substantial benefit to
patients with identified deficits of ADAMTS13 or
factor H.
• It may also be considered in patients with other
genetic forms of HUS
 Eculizumab
• It is an anti-C5 antibody that inhibits complement
activation(a pathway that contributes to active
disease in some forms of atypical familial HUS; this
pathway may also contribute to the process in STEC-
HUS)
• FDA approved for the treatment of atypical HUS.
• Because of the risk of meningococcal disease in
patients with defects in terminal complement
components, it is recommended to give the
meningococcal vaccine prior to giving eculizumab (if
the patient has not been primarily immunized).
What studies say?

Source :INTERNET
HUS Epidemic Europe 2011
O 104:H4
 Prognosis
• With early recognition and intensive supportive care, the
mortality rate for diarrhea-associated HUS is < 5%
• Recovery of platelet counts usually occurs first, followed by renal
recovery about 5 days later, and finally by resolution of anemia.
• Most recover renal function completely, but of surviving
patients, 5% remain dependent on dialysis, and up to 30% are
left with some degree of chronic renal insufficiency.
• The prognosis for HUS not associated with diarrhea is more
severe.
• Pneumococci associated HUS causes increased patient morbidity
(>80% require dialysis), with the mortality rate reported as 20%
• The familial, genetic forms of HUS can be insidiously progressive
or relapsing diseases and have a poor prognosis
 Prognosis
• Most patients with diarrhea-associated HUS recover
completely, with little risk of long-term sequelae.
• Patients with hypertension, any level of renal insufficiency,
or residual urinary abnormalities persisting a year after an
episode of diarrhea-positive HUS (particularly significant
proteinuria) require careful follow-up.
• Patients who have recovered completely with no residual
urinary abnormalities after 1 yr are unlikely to manifest
long-term sequelae.
• Because of some reports of late sequelae in such patients,
annual examinations with a primary physician are still
warranted
SUMMARY
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