Atypical hemolytic uremic

syndrome

Prof. Dr. med. Lars Pape

Definition HUS:

hemolytic anemia

Thrombocytopenia

acute renal failure

• main cause of acute renal failure in children

• Incidence 1 – 2 / 100 000 children

• highest incidence in Argentinia

• 90 % by Shigatoxin producing E.coli (EHEC)

• 10 % „atypical“ HUS

Thrombotic Microangiopathies1. Infection

a. Shiga-Toxin producing bacteria(EHEC, Shigellen, Citrobacter) = STEC-HUS

b. Strep. pneumoniae

2. Dises of the complement system (and others) = aHUSa. genetic causeb. caused by antibodies

3. ADAMTS13 deficiency = TTPa. Genetic causeb. Caused by antibodies

4. others (HELPP, post-Tx, iduced by medication...)

The complement system: always on, strongly amplified, dependent on natural regulators

The complement system is a vital component of the natural (innate) protective immune systemComplement is activated by three mechanisms (classical, alternative and lectin) which allow the system to respond to inflammatory, infectious, ischaemic and necrotic insult, as well as foreign and self-antigens•Always ‘on’ to allow rapid immune response

– Rapid amplification leads to powerful and destructive immune reactions

– Natural inhibitors of complement keep amplification in check and prevent uncontrolled complement activation

Factors that amplify complement activation

Infection Surgery

Autoimmune Pregnancy

Ongoing research in the field of complement inhibitors• Most genetic mutations have been discovered in the past 20 years• 30–50% of patients with aHUS have no identifiable genetic mutation

Link with low C3

Homozygous CFH deficiency

CFI mutations

C3mutations

Link with RCA –CFH mutations

(SCR20) Thrombomodulin mutations

Hybrid (CFH-CFHRI)

Heterozygous CFH deficiency

Association with low CFH

MCPmutations

Anti-FH auto-antibodies

Homozygous MCP deficiency

CFB mutations

1973 1981 1994 1998 2003 2004 2005 2006 2007 2009

DCFHR1 / DCFHR3 deletion

Noris & Remuzzi, NEJM 2009

aHUS

AnaphylaxisInflammationThrombosis

ConsequencesCell destruction

InflammationThrombosis

Consequences

Prox

imal

Term

inal

Lectin pathway Classical pathway Alternative pathway

Immune complex clearanceMicrobial opsonisation

C3a

iC3b

C3

C3bWeak anaphylatoxin

C3 + H2O: always active (chronic)Amplification

Gain of Function Mutations: C3, CFB

+

Chronic uncontrolled complement activation leads to devastating consequences in aHUS

C5a

Potent anaphylatoxin Chemotaxis Proinflammatory Leukocyte activation Endothelial activation Prothrombotic

C5b-9Membrane attack complex

Cell lysis Proinflammatory Platelet activation Leukocyte activation Endothelial activation Prothrombotic

C5C5b

C6C7

C8C9

C5-convertase

Natural Inhibitors: Factor H, I, MCP

Thrombomodulin

Endothelial cells: - Activation - Swelling and disruption

Platelets:- Activation- Aggregation

Leukocytes:- Activation

Platelet consumptionMechanical haemolysis

Blood clotting Vessel occlusion

InflammationIschaemia

Systemic multi-organ complications

Clinical consequences:

Red cells:-Haemolysis

Uncontrolledcomplement

activation on cells

Chronic uncontrolled complement activation leads to endothelial and end organ damage

aHUS

aHUS is asystemic disease !

• Kidney

• CNS

• Lung

• Heart

• Vessels

Plus one or more of the following:

Differential diagnosis for TMAs: aHUS, TTP and STEC-HUS

Evaluate ADAMTS13 activity and Shiga-toxin / EHEC test

ThrombocytopeniaPlatelet count <150,000 or

>25% decrease from baseline

Renal impairmentElevated creatinineand / orDecreased eGFR and / or

Elevated blood pressure and / or Abnormal urinalysis

Neurological symptomsConfusion and / orSeizures and / or

Other cerebral abnormalities

Gastrointestinal symptomsDiarrhoea +/– blood and / or Nausea / vomiting and / or

Abdominal pain and / orGastroenteritis

Microangiopathic haemolysisSchistocytes and / orElevated LDH and / or

Decreased haptoglobin and / orDecreased haemoglobin

AND

Serum creatinine level ≤200 µmol/L or platelet count ≤30×109/L had the stronger association with a severe ADAMTS13 deficiency

Patient characteristicsADAMTS13

Deficiency group (n=160)

ADAMTS13Detectable group

(n=54)p value

Platelet count, ×109/L 17.4 (14.2) 66.6 (49.3) <0.0001Creatinine level, µmol/L

mg/dL114 (68.4)1.29 (0.77)

454 (326)5.13 (3.68)

<0.0001

Patient characteristics Adjustedodds ratio 95% CI p value

Platelet count ≤30×109/L 23.4 3.4–24.2 <0.001Creatinine level ≤200 µmol/L(2.26 mg/dL) 9.1 8.8–62.5 <0.001

Creatinine and platelet count can support a differential diagnosis of aHUS

First diagnostic steps

Hb, LDH, freee Hb, PLT, Haptoglobine, FragmentocytesGOT, GPT, GlDH

Creatinine, BUN, Cystatine C

Renal Ultrasound (RI 1) !

Eventually: EEG / CCT

Exclusion TTP

Terminal complement complex

Faktor H, B, I

Faktor-H antibodies

Status of complemet system

PE / PI is not associated with positive long-term outcomes regardless of mutation

Affected protein Short-term outcome to PE / PI*

Factor H 60%

CFHR1, R3 70–80%

MCP No definitive indication for therapy

Factor I 30–40%

Factor B 30%

C3 40–50%

THBD 60%

Long-term outcome to PE / PI*

Death or ESRD: 70–80%

ESRD: 30–40%

Death or ESRD: <20%

Death or ESRD: 60–70%

Death or ESRD: 70%

Death or ESRD: 60%

Death or ESRD: 60%

Eculizumab blocks terminal complement

C5

Prox

imal

Term

inal C5a

Eculizumab

• Proximal functions of complement remain intact– Weak anaphylatoxin– Immune complex clearance– Microbial opsonisation

• Terminal complement –C5a and C5b-9 formation blocked

• Eculizumab binds with high affinity to C5

Complement cascade

C5b-9C5b

C3 C3a

C3b

Rapid and Sustained Improvement in Platelet Count under Eculizumab

164 x 109/L: Mean Change from Baseline in Platelets at Week 27

*P<0.0001

0

25

50

75

100

125

150

175

200

225

250

275

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

Plat

elet

Mea

n C

hang

e fr

om B

asel

ine

Weeks

**

*

* **

**

* *

Plat

elet

Cha

nge

from

Bas

elin

e†(x

109 /L

)

Study Week

Significant and Continued Improvement in eGFR under Eculizumab

64 mL/min/1.73m2: Mean Change from Baseline in eGFR at Week 27

-15

5

25

45

65

85

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

eGFR

Cha

nge

from

Bas

elin

e†(m

L/m

in/1

.73m

2 )

*

** *

*

**

*

*

Study Week

*P<0.001#P<0.05#

82% of Patients Eliminated Dialysis under Eculizumab

% Discontinued Dialysis

Patients Not on Dialysis at Baseline:

Of the 11 patients not on dialysis at baseline, all patients (100%) remained dialysis-free through the end of the study evaluation period

9/11

Patients on Dialysis at Baseline

Adverse Event Findings

C10-003 (N=22) AEs occurring in ≥20% n (%)

Pyrexia 11 (50)

Cough 8 (36)

Abdominal pain 7 (32)

Diarrhea 7 (32)

Upper respiratory tract infection 7 (32)

Vomiting 6 (27)

Nasopharyngitis 6 (27)

• Most AEs were mild or moderate• No meningococcal infections in this

trial• One patient was noted to have low

positive values for neutralizing antibodies to eculizumab

– Overall, there had been no observed correlation of antibody development to clinical response or adverse events

• No new safety concerns• No deaths

aHUS caused by factor H antibodies• an immunsuppressive therapy with Steroids, Mycophenolatmofetile

and/or Rituximab can be tried.• Cave: Rituximab can not be administered in parallel with Eculizumab,

because Eculizumab inhbits the complement need for destruction of B-cells

• In case of negative factor H ab after immunosuppressive tretament Eculizumab may be discontinued.

• After transplantation mosty no recidives under maintanance immunosuppression, therefore no long-term Eculizumab therapy needed.

• Factor H-antibodies can develop, if in patients with factor H-deficieny or mutation, factor-H is regularily administered by plasma infusion or plasmaexchange therapy.

What to do initially?• If differential diagnosis is unclear, immediate start of plasma-exchange

therapy as this is therapy of choice in TTP.• In children with clear diagnosis of aHUS immediate treatment with

Eculizumab• If the diagnosis of TMA is unclear: renal biopsy• After exclusion of TTP and typical HUS: immediate administration of

Eculizumab• If there is a massive complement activation in complement diagnostics

(i.e. highly elevated terminal complement complex): immediate treatment with Eculizumab

• If anti-Factor H Ab are diagnosed: Switch from Eculizumab to intensive immunosuppressive treatment