5-3. Atypical HUS. Rosanna Coppo (eng)

Rosanna CoppoAlessandro AmoreTorinoItaly

Atypical HUS:diagnosis, treatment, outcome

Hemolytic uremic syndrome (HUS) a disease of the microvessels

Thrombotic

microangiopathy

• Thrombocytopenia

• Fragmented red cells, schistocytes

• Intravascular haemolysis

• Renal failure of various severity

Moschowitz’s Thrombotic

Thrombocytopenic Purpura (TTP)

(neurological symptoms,

limited renal damage)

Gasser’s

Hemolytic-Uremic Syndrome (HUS)

(renal damage, few neurological symptoms)

The endothelial cell

is the thrombotic microangiopathy target

Endothelial cells Small arteriola

Thrombotic Microangiopathy :

Change in the endothelium-platelets balance due to an anatomical and functional alteration of endothelium

2011 Orphanet Frameaux-Bacchi

Infection-induced

Athypical HUS

Verotoxin induced Thrombotic Microangiopathy

E. Coli O157-H7: verotoxin (shiga-like toxin VTEC) found in 50%

of sporadic HUS and in 90% of epidemic HUS

50 serotypes of E. Coli( O111: H neg; O26: H11)

Shigella, Salmonella, Streptococcus, etc

Typical HUS in children:

10

VTEC-induced enteropathyIntestinal epithelium

Enteral vessel

Distruction of brush border: diarrhea

cytotoxic damage involving vessels: intestinal hemorrhages

E.Coli

11

Vessels

VTEC

polymorphonucleates

Gb3

plateletsGb3

endothelium

platelets activation

cytokines,prostanoids,chemokines

• platelets recruitment • parietal thrombus incresase• damage amplification loop

progressive vascular occlusion

Shear stress

Shear stress

shear stress due to parietal thrombus induces intravascular mechanical hemolysis with

skystocytis formation

Parietal thrombus.red blood cell fragmentation

Skystocytes

low platelet count, hemolytic anemia (negative Coomb’s test)

genetic HUS

Complemet pathway is continously activated at subliminar level

C3b circulates in the blood stream and can bind to endothelial cell receptors

Abnormalities in complement cascade can induce endothelial cell damage

Complement and endothelial damage

endothelial surfaceInhibitors:

CFHCFI

in plasma

MCP bound to

cell surface

Complement disorders and athypical HUS

Genetic HUS

Defective H factor (CFH). This plasma protein binds to host cell surfaces and prevents formation of C3bBb , the C3 convertase, by factor B.

the result is uncontrolled C3 activation and endothelial damage (gene on chromosome 1q).

Early in life, sometimes low C3 , hypertension, high risk of relapse, poor prognosis in 50%.

80% risk of recurrence and graft loss

Genetic HUS

Defective FI (a co-factor for FH) cleaves C3b interrupting the cascade before C5a

FI circulates in plasma using FH, MCP or CR1 as co-factors. Heterozigous patients have low FI levels.

MCP (membrane cofactor protein), a membrane-bound regulator, which cleaves C3b and C4b on host cells, expressed in glomerular endothelium aslo acts as co-factor of FI.

30%

10%

5%

Diarrhea negative HUS constitute 10-30% of HUS .(genetic mutation of complement components 10-15%)

ADAMTS 13 and thrombotic microangiopathy

Eculizumab anti C5 monoclonal antibody

Eculizumab 20 mg/kg

Family history

• Both parents and 2 older twin brothers in good health

• The child’s aunt (mother’s sister)- At 26 years of age, june 1998: normal routine lab. data.- September 1998: Cr 2-4 mg/dl - hypertension

Hb 5 g/dl - Plts 150.000/mm3

Diagnosis of HUS- 26 PE : Cr 4-2 mg/dl - Plts 250.000/mm3

- ESRF in March 2000 start HD - No recurrence of hemolysis

(stable Plts 300,000, stable LDH 300 U/L)- HT controlled, now normotensive- No mutations detected.- No inclusion in transplant list

AD at the age of 6 months: after febrile URT infection, gross hematuria and paleness

• Diarrhea negative

• Plts 50.000/mm3

• Severe anemia (Hb 6.6 g/dl)

• Fragmented erythrocytes 20%

• LDH 9.000 U/L

• C3 95 mg/dl ; C4 22mg/dl

• Serum creatinine 1.0 mg/dl (eGFR 30 ml/min/1.73m2)

He was treated with plasma infusions (9x 10 ml/kg)

HUS

Heterozigous 3645C>T mutation

Resulting in amino acid change S1191Lin the terminal portion SCR20 of the CFH protein

Genetic analysis was then performed (Bresin E, Bergamo):A complement factor H mutation was found in the child, his mother, his aunt and his grand-mother

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LDH (U/L)

1 2 53 4

9 P 17 P 16 P 7 P

PE 6 PE 1 PE 7 PE 2/week, then 1/week, then stop

P 2/week

P PE Plasma infusions 10 ml/Kg Plasma exchange >1. 5 plasma vol

6 P

PE 6

Exit site PD catether staphilococcal infection

P 1/week

FeverFever

SERUM CREATININE (mg/dl)

00.5

11.5

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33.5

44.5

1 13 25 37 49 61 73 85 97 109 121 133 145 157 169 181 193 205

PD 7 days PD 15 days

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LDH (U/L)

SERUM CREATININE (mg/dl)

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P PE Plasma infusions Plasma exchange

5 P

PE 4 PE 1/week

2 P

PE 6 PE 1/week

1sth CVC infectionStaphilococcus

2nd CVC

infection(Rizobium

radiobacter)

3rd CVC infection

G- sepsis

PD

PE 2-3/week

• From the age of 2 years chronic peritoneal dialysis with 2 more HUS relapses Afterwards no more relapses of HUSPE suspendend 5 months laterRepeated peritoneal catheter infections

• From the age of 3 years switched to haemodialysis following fungual peritonitis

• No more relapses of HUS• No signs of haemolisis • Repeated CVC infection

On August 5 2011 immediately before kidney transplant when he was 5-year-old he was treated with 600 mg of eculizumab (body weight 18 Kg) Then we infused eculizumab on post-transplant day 1 (300 mg) and 7 (600 mg), and every other week thereafter (300 mg). He was induced with low-dose thymoglobulin and basiliximab, and maintained on steroid, cyclosporine and mycophenolate mofetil. His renal function promptly recovered to normal range.

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plt x

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0/ u

l

transplant

Eculizumab 600 mg e.o week BW - 18 kg (before

kidney transplant, 5.08.2011)

Complement and innate immunity

Treating a child with atypical HUS is still a challenge. We are planning for this child a liver transplantation under the effect of eculizumab

• Thank you