Download Slide 1

Hemolytic Uremic Syndrome
Beatrice Goilav, M.D.
Pediatric Nephrology
Children’s Hospital at Montefiore
Albert Einstein College of Medicine
Disclosures
Nothing to disclose.
Outline
Background/Epidemiology and other
things to know on “classical” diarrheaassociated HUS
The “funky” types of HUS

Atypical, non-diarrhea associated, recurrent,
familial
What you should know about atypical HUS
and what to do with that information
THE HISTORY OF HUS
Gasser C, et al. 1955
First description

Self-limited illness associated with a
prodrome of diarrhea that results in
Einstein’s first job was here
spontaneous recovery
I was born here
Conrad Gasser (1912-1982)
DIAGNOSTIC COMPONENTS
AND
HISTOPATHOLOGY
Hemolytic Uremic Syndrome (HUS)
Triad

Microangiopathic hemolytic anemia

Thrombocytopenia

Acute kidney injury
Thrombotic Microangiopathy (TMA)
Hemolytic Uremic Syndrome
Thrombotic Thrombocytopenic Purpura
Hemolytic Anemia
Microangiopathic hemolytic anemia with erythrocyte
fragmentation
Coombs negative
Plasma LDH elevated
Haptoglobin decreased
Most sensitive marker to track resolution of intravascular
hemolysis


Severity does not correlate with clinical outcome
Red cell production increased
Thrombocytopenia
Variable and transient

May be missed
Consumption of platelets
Majority of platelets removed in
reticuloendothelial system
Significant bleeding rare!

Slightly pro-thrombotic state
Acute Kidney Injury
Abrupt
Oligoanuria
Proteinuria
Hypertension


Severe and difficult to control in atypical forms
Absent or mild in infection-associated form –
delayed to recovery period
Thrombotic Microangiopathy
(TMA)
Histopathological term
Characterized by presence of
Platelet-fibrin thrombi within the vascular lumen
Injury to endothelial cells with separation from
underlying basement membrane
Deposition of eosinophilic material
Risk Factors for Development of HUS
Female gender
Severe colitis
Fever
Leukocytosis
Also:




Younger age
Antimotility agents
Antibiotics
Alterations in gene for factor H
Implicated in pathophysiology of atypical HUS
Some Statistical Data
Most common cause of acute kidney injury in
childhood

Incidence: 3-5/100,000 population in children age 118
Gradual decline from early childhood to adolescence
Significant morbidity and mortality in acute
phase
Mortality: 3-5%, usually associated with severe extra-renal
disease
Primary diagnosis for up to 4.5% of children on
chronic renal replacement therapy
M&M
Mortality
3-5%
Serious extra-renal complications
20%
Need for acute dialysis
40%
Persistent renal injury
20%; hypertension, proteinuria, reduced GFR
Terminology/Categories
Term
Comment
D+ HUS
Patient presents with prodrome of diarrhea in past 2
weeks
Typical HUS
D+ HUS, diagnosis made in retrospect; single, selflimited event
Atypical HUS
Any pattern of clinical presentation other than D+
HUS – implies complement dysregulation
Recurrent or relapsing HUS
Repeat episode of same clinical features, implies
repeat injury to kidneys – strongly suggests genetic
or autoimmune risk factor
Thrombotic microangiopathy, glomerular
thrombotic microangiopathy
Pathological descriptive terms
Familial HUS
Unclear term. Not distinguishing between
Synchronous HUS = several family members
infected with EHEC at the same time;
and
Asynchronous HUS = implies inherited risk factor
D+ HUS
Diagnosis
Clinical - Abrupt onset of illness
Recognized within 24 hours of onset



Lethargy
Pallor
Oliguria
Laboratory abnormalities:
Coombs-negative anemia and thrombocytopenia
Rising BUN/Creatinine
Elevated LDH
Low haptoglobin
Clinical Time Course
Ingestion of bacteria
Enterocolitis within 2-3 days
Bloody stools in >85%
Fever
Severe abdominal pain
Most cases: self-limited, complete resolution
5-10% progress to HUS
Monophasic illness
Route of Infection
Most Common Etiology Worldwide
Enterohemorrhagic E. coli (EHEC)
O157:H7
D+ HUS (typical)
Produces Shiga toxin (Stx) 1 and/or 2

Encoded on a phage
Other E. coli strains also produce Stx


Called Stx-producing E. coli (STEC)
Over 400 seropathotypes
Pathogenesis
Shiga toxin (Stx)-induced injury to
endothelial cells
Activation of prothrombotic coagulation
cascade
Release of inflammatory mediators and
chemokines
Molecular Risk Assessment
Association of virulence genes with severity of
disease
Presence or absence of genes (binary typing)
produces genetic fingerprint for each isolate
Identify strains that have greater potential to cause
harm = molecular risk assessment
Binary Typing of Virulence Genes
Distribution of 41 virulence genes in STEC
isolates


“Virulence bar code” for each isolate
Integrated epidemiological data
Allows some prediction of clinical course
Brandt SM et al. Appl Environ Microbiol. 2011 Apr;77(7):2458-70.
Brandt SM et al. Appl Environ Microbiol. 2011 Apr;77(7):2458-70.
Virulence Factors
Seropathotype (SPT) classification identifies STEC
serotypes linked to outbreaks and/or serious
disease




SPT A (O157:H7, O157:NM) and SPT B (O26:H11/NM, O103:H2,
O111:H8/NM, O121:H19, O145:NM) associated with outbreaks
and HUS
SPT C (e.g., O5:NM, O91:H21, O113:H21, O121:NM, O128:H2)
associated with sporadic cases of HUS but not with outbreaks
SPT D includes remainder of STEC serotypes that have been
reported to cause sporadic disease and association with diarrhea
but not HUS
SPT E not associated with human illness
Therapy
Nothing proven
Intensive, supportive medical care
Dialysis if:
Anuria x 24 h
Oliguria (urine output <0.5ml/kg/h) x 48-72 h
pRBC Transfusion if:
Hemoglobin <6 g/dl
Ineffective treatments are:

Antiplatelet drugs, fibrinolytic agents, IVIG, high-dose
steroids, plasmapheresis, and oral Stx-binding agents
Careful Monitoring
Electrolyte abnormalities


Hyponatremia
Hypocalcemia
LDH, serum creatinine, Hgb, platelets
Watch out for :
Seizures
Pancreatitis
Myocardial dysfunction
Adult respiratory distress syndrome
Sudden neurologic deterioration
Prevention of HUS –
The Scientific Approach
Subcutaneous mouse vaccine against stx
and intestinal zonula occludens toxins



Decreased shedding of E. coli O157:H7
Good news: mice TOLERATED vaccine
WELL
Bad news: MICE tolerated vaccine well
Prevention of HUS –
The Useful Approach
Changes in feed provided to cattle
Tighter regulation of meat processing plants
Irradiation of food and beverages
No antibiotics in children with bloody diarrhea
Prompt hospitalization and administration of
isotonic parenteral fluids
Prevent vascular injury in glomerular microcirculation
Isolate sick individual from other family members
D- HUS
Atypical, Sporadic, Non-Familial
HUS
Pneumococcus-related disease
Younger children
Number of cases requiring dialysis is higher
Worse prognosis compared with STEC-related
HUS
Other causes:
HIV infection, use of calcineurin inhibitors, OCP, SLE (usually
in presence of antiphospholipid syndrome), and HELLP
syndrome
Atypical HUS
Atypical HUS
Annual incidence of genetic forms of aHUS:
10% of D+HUS
3-5 cases per 1 million
Strong association between aHUS and
mutations and/or polymorphisms in complement
gene (regulatory and activation proteins)
50% of cases linked to genetic mutations in
alternate cascade
Modulators of Alternate
Complement Cascade
Loss-of-function mutations in regulatory proteins
or gain-of-function mutations in factor B and
complement 3
Three most common defects:
Mutation in factor H: 25-35% not to be confused with
Mutation in factor I: 5-10%
Mutation in membrane co-factor protein (MCP = CD46): 3-5%
Deficiency in factor H-related proteins (CFHR15)


Polymorphic delCFHR1/3 deletion strongly associated with CFH autoantibodies
aHUS due to CFH auto-antibodies more common in children
Clinical Course of aHUS
Onset of syndrome frequently preceded by
environmental insult (e.g., infection)
Typically infants/young children
C3 level may be normal

CFH mutations predominantly result in
impaired ability of CFH to interact with cell
surfaces, but ability to regulate plasma C3
preserved
Clinical Relevance of
Genetic Testing
Important to test for CFH auto-antibodies strategies to reduce auto-antibody titer (e.g.
plasma exchange)
Higher relapse rate
Increased likelihood of progression to end-stage
kidney disease
High rate of recurrence after kidney transplant
Factor H or I mutation >> MCP mutation
MCP present in transplanted kidney – prevents
complement-mediated injury to allograft
Therapy of Genetic aHUS
Plasma
Intermittent infusions or via plasmapheresis
Treatment intensity guided by disease activity:
Platelet count
LDH level
Serum creatinine concentration
If suspecting genetic form of aHUS, initiate daily
plasma therapy promptly
Combined kidney/liver transplant
For cases with factor H and factor I mutations
Hepatic production of normal complement regulators
Plasma Therapy
Not THIS one!
Plasma Therapy
Complement 5 Protein
Critical role in development of aHUS
CFH-deficient animals expressing mutant CFHD16–20 protein
develop spontaneous aHUS
C5 knockout in this model results in resistance to aHUS.
Eculizumab
Recombinant, humanized, monoclonal Ab produced from
mouse myeloma cells
Approved for treatment of paroxysmal nocturnal
hemoglobinuria (PNH)
Reduces intravascular hemolysis, anemia, thrombotic
events, and transfusion requirements in PNH
Targets complement protein C5 and prevents generation
of proinflammatory peptide C5a and cytotoxic membrane
attack complex C5b-9
Regimen
Weekly infusions with gradual increase in dosing with
biweekly maintenance therapy
Shown to completely block complement activity
Complement blockade confirmed by CH50
measurements
Dosing and pharmacokinetics in children are underway
in international multi-center study – Children’s Hospital at
Montefiore to be added as site within next 2 months
Thrombotic Thrombocytopenic
Purpura
TTP – Moschcowitz Syndrome
An acute febrile pleiochromic anemia with hyaline thrombosis of terminal
arterioles and capillaries: An undescribed disease. Archives of Internal
Medicine, Chicago, 1925, 36: 89.
Deficiency of von Willebrand Protease
(ADAMTS13)
= a disintegrin and metalloproteinase with a thrombospondin type 1 motif,
member 13
Thrombocytopenia
Microangiopathic hemolytic anemia
Neurological symptoms
Renal dysfunction
Fever
Role of ADAMTS13
(or a disintegrin and
metalloproteinase with a thrombospondin type 1 motif, member 13)
ADAMTS13
Deficiency
(you know what is supposed to be written
here)
Cause:
Rare: loss-of-function mutation (Congenital TTP)
Acquired inhibitor: IgG auto-antibody

Associated with use of Clopidogrel and Ticlopidine
Effect:
Ultra-large vWF multimers
ADAMTS13
(guess what?)
Deficiency
Enzyme activity of <5% is primary cause of
microvascular thrombosis
Enzyme activity <30% in several disease and
physiological states
Thrombi found at arteriolar-capillary junction – area of
high shear stress
Affected organs:
Brain, heart, spleen, kidney, pancreas, adrenals, lungs, and eyes
Outcome of TTP
Mortality:
Historically: 95%
Today: 20%
What made the difference?
Plasma therapy
The Weird Ones
HUS can be also caused by:

Cobalamin deficiency


Quinine/Quinidine



Defect in methylmalonic aciduria and homocystinuria
gene (MMACHC)
Found in tonic water and tablets that prevent muscle
cramps
Autoantibodies to ?
Really rare ones:


Use of anti-VEGF monoclonal antibodies
Disseminated adenocarcinoma
Questions?
Not related to me, no idea who he is, but love his hair