Atypical Hemolytic Uremic Syndrome – a new era of treatment?

Dr Stella Chim

Queen Mary Hospital

Hong Kong Paediatric Nephrology Society

2018-09

Case presentation

Background

M/4 years old Gestation 35 weeks Emergency Caesarean section x severe IUGR Birth weight 1.325 kg Medical history: Anaemia treated with iron and folate supplement in

neonatal period (no haemolysis, normal bone marrow response)

History

1st episode of atypical HUS at 17 months old

Initially presented with gastroenteritis, given

symptomatic medication from private doctor

On day 4 of fever, developed 4 episodes of generalised

tonic-clonic seizures

Suspected enterovirus-related encephalitis

CT brain: no focal lesion

CSF biochemistry, cultures not suggestive of meningitis

Investigations:

Microangiopathic haemolytic anaemia

Thrombocytopaenia

Acute kidney injury

Deranged liver function

Raised LDH, urine haemastix large (RBC < 30/ul)

Clinically suspicious of thrombotic thrombocytopaenic purpura (TTP)

ADAMTS13 activity only marginally low —> not suggestive of TTP

In view of near normal ADAMTS13 activity, absence of autoantibody against

ADAMTS13 and prominent renal impairment, suspected haemolytic uraemia

syndrome

Workup for haemolytic uraemia syndrome

NPA: H1 influenza A virus detected

Stool x Enterovirus, Norovirus, Rotavirus negative

Stool bacterial C/ST negative

Urine x streptococcal antigen negative

T-antigen activation (pneumococcal associated HUS) negative

—> atypical HUS (aHUS)

Started methylprednisolone, later switched to oral prednisolone

Total 7 sessions of therapeutic plasma exchange done

Acute kidney injury with creatinine up to 313 umol/L and

oliguria, requiring renal replacement therapy (CVVHDF for 6

days, PD for 14 days)

Complete haematological recovery after plasma exchange, liver

function normalised

Renal function returned after 1 month. No need for chronic

dialysis

5.5 12.6 11.2 8.3 7.3 7.2 10.8 12.9 13.9 12.8 12.8 12 12.3 12.4 10.8 11.5 11.1 10 11.1 10

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18/2 19/2 20/2 21/222/2 23/224/2 25/2 26/2 27/2 28/2 29/2 1/3 2/3 4/3 6/3 7/3 10/3 13/3 14/3

Creatinine Platelet Haemoglobin

Plasma exchange

Methylprednisolone Prednisolone

Peritoneal dialysis CVVHDF

Overseas genetic testing for aHUS No known pathogenic mutations for CFH, CFI, MCP,

C3, CFB, THBD, DGKE genes Anti-factor H autoantibodies not detected C4 slightly slow, C3 normal, factor H normal Complement factor I 14 mg/L (21-40)

2nd episode of aHUS at 30 months old

Presented with fever and coryzal symptoms

Clinically rhonchi and crepitations bilaterally

Associated with on-off diarrhoea

NPA: metapneumovirus detected —> treated as viral

pneumonitis

After admission, noted 3 episodes of abnormal eye

movement with uncontrolled upward gaze

No seizure or loss of consciousness

Urine occult blood moderate

Investigations

Microangiopathic haemolytic anaemia

Thrombocytopaenia

Deranged renal function

Raised LDH, urine haemastix moderate (RBC <30/ul)

Stool x Enterovirus, Norovirus, Rotavirus negative

Stool bacterial C/ST negative

Throat swab commensals

T-antigen negative

ADAMTS13 activity normal

Treated as recurrent aHUS

Given 3 doses of Eculizumab on 25/2/2017, 4/3/2017 and

24/3/2017

Already received Haemophilus influenza B and Pneumoccocal

vaccine. Given Penicillin V as meningococcal prophylaxis before

giving Eculizumab

Did not require plasma exchange or RRT

Gradual resolution of anaemia and thrombocytopaenia. Renal

function normalised

Received quadrivalent meningococcal vaccine and

meningococcal B vaccine on follow-up

3rd episode of aHUS at 3.5 years old Presented with fever and coryzal symptoms NPA Influenza B positive, given Tamiflu

Red cells fragments, raised LDH, urine haemastix trace/neg, Cr normal (14-15 Feb 2018) dropped in platelet dropped in Hb raised creatinine

Noted 1 episode of abnormal eye movement with vertical movement of eyes

No seizure or loss of consciousness Proceeded to Eculizumab infusion in view of

haemolysis, given on 15/2/2018, 22/2/2018 and 8/3/2018

Haemolytic picture resolved, platelet count normalised

Diagnosis of Hemolytic Uremic Syndrome (HUS)

Diagnosis of HUS

Microangiopathic hemolytic anemia

Thrombocytopenia

Acute kidney injury

Peripheral smear in microangiopathic hemolytic anemia

The smear shows multiple helmet cells (arrows) and other fragmented red cells (small arrowhead); microspherocytes are also seen (large arrowheads). The platelet number is reduced; the large platelet in the center (dashed arrow) suggests that the thrombocytopenia is due to enhanced destruction.

Normal peripheral blood smear. Several platelets (arrows) and a normal lymphocyte (arrowhead). The red cells are of relatively uniform size and shape; central pallor (dashed arrow) should equal one-third of its diameter.

Management of atypical HUS

Atypical hemolytic uremic syndrome (aHUS) in the last decade

In under a decade, complement alternative pathway (AP) dysregulation has emerged as the major cause of aHUS

Facilitated development of novel, rational treatment options targeting terminal complement activation

E.g. using an anti-C5 antibody Eculizumab

Propose a diagnostic and therapeutic approach for aHUS in children

Introduction

Complement alternative pathway (AP) dysregulation is responsible for 60-70% of cases of aHUS

Genotype-phenotype correlations

More precise definition of aHUS HUS without coexisting disease

Identified mutations in gene encoding diacylglycerol kinase (DGKE) suggest complement-independent forms of aHUS

Introduction

Plasma therapy was mainstay of treatment for aHUS until 2009

Since 2009, 4 prospective trials and over 80 case reports on the effective terminal complement blockage with eculizumab

Rescue native kidney function or allow successful kidney transplantation after renal loss due to aHUS

Definition of atypical HUS

Etiology and pathophysiology-based classification of various forms of thrombotic microangiopathies (TMA)

Emerging agreement among haematologists and nephrologists that aHUS should be reserved for HUS without coexisting disease

Etiology-based classification of TMA

ADAMTS13: A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13 STEC: Shiga toxin-producing E coli; CFH: complement factor H; CFI: complement factor I; MCP: membrane cofactor protein (CD46); CFB: complement factor B; THBD: thrombomodulin

Diagnostic algorithm for aHUS in children

• Blood sampling before plasma exchange/plasma infusion

Diagnostic algorithm for aHUS in children

• Blood sampling before plasma exchange/plasma infusion

Complement investigations in aHUS

60-70% of aHUS patients carry currently identifiable mutations in complement genes or anti-CFH antibodies (2 large series)

Resulted in loss of protection of endothelial cells and platelets from complement attack TMA lesions

Normal C3, C4, CFH and CFI plasma levels do not exclude the diagnosis of complement dependent – HUS

Decreased C3 level observed in acute phase of STEC-HUS & Streptococcal Pneumoniae-HUS

Decreased C3 observed in 30-40% of aHUS

Levels of C5a and soluble C5b-9 (sC5b-9) are elevated in acute phase of aHUS, may be biological markers to differentiate aHUS from TTP

Who should undergo genetic screening, when & why?

Treatment options in pre-complement blockade treatment era

Plasma exchange/plasma infusion

Uncertain benefit

Technique-related complications in children

Sensitized to plasma components

Kidney transplantation

Terminal complement blockade treatment: Eculizumab

A monoclonal humanized anti-C5 antibody

Prevents C5 cleavage and the formation of C5a and C5b-9

Blocking the C5a pro-inflammatory and C5b-9 pro-thrombotic consequences of complement activation

100 patients treated within 4 prospective, open-label, single-arm trial

80 more case reports

Drawback

Risk of meningococcal infection

Immunity against Neisseria meningitis depends on the lytic terminal complement complex C5b-9

Meningococcal vaccines are recommended

Antibiotic prophylaxis is recommended before completion of vaccines

Very expensive self finance item

Life long treatment and possible development of neutralizing antibodies

Recommended eculizumab dosing for aHUS

Cost:

300mg / vial

HK$ 52310.16

Self finance item in HA

From 2018, supported by

Community Care Fund

Medical Assistance Programme

“Subsidy for Eligible Patients to Purchase Ultra-expensive Drugs (Including Those for Treating Uncommon Disorders)”

Efficacy of eculizumab in aHUS

Systematic review of 1st two trials in UK

Indicated eculizumab was highly effective in aHUS

Despite study design limitations

Possibility of biased selection

Lack of control group

Lack of use of surrogate markers

In trial 3 (children; early initiation)

The “best of all” recovery of renal function observed in children with early treatment initiation

Efficacy of eculizumab in aHUS

Eculizumab effective in both groups of patients with or without complement mutation, but more % of patients with complement mutation responded

Eculizumab effective to treat or prevent post-transplant recurrence of aHUS

Risk of meningococcal infection under eculizumab

Immunity against Neisseria meningitis depends on the lytic terminal complement complex C5b-9

Prevention of meningococcal infection crucial

Vaccination / antibiotic prophylaxis

Clinical practice recommendations for patients with aHUS in 2014 Children with clinical diagnosis of aHUS propose eculizumab

as first-line treatment

To avoid plasma exchange and complications of central venous catheters

Confirmation of a complement mutation is not required prior to treatment initiation

Undue treatment delay may affect ultimate renal recovery & increase risk of early progression to ESRD

Should be initiated within 24-48 hrs of onset or admission

If eculizumab not available, plasma exchange should be started as in 2009

Clinical practice recommendations for patients with aHUS in 2014

Genetic screening is required for longer-term management of patients

Anti-CFH antibody – only complement investigation urgently needed during acute phase, as positive additional treatment options

Consider combining plasma exchange (PE) with eculizumab + steroid + immunosuppressive agent

Is life-long complement blockage treatment recommended?

Discontinuation of Eculizumab for a HUS: report of 10 cases Ardissino et al. Am J Kid Dis 2014;64(4):633-637

10 discontinued eculizumab 3 relapsed within 6 weeks

Resumed immediately all 3 fully recovered

Risk of aHUS relapse after eculizumab discontinuation Fakhouri et al. Clin J Am Soc Nephrol 2017;12:50-59

Eculizumab discontinued in 38 (9 children 29 adults) of 108 patients (median treatment duration 17.5 months)

55% carried novel or rare complement genes variants

Renal recovery under eculizumab equally good with or without complement gene variants

Median FU 22 months 12 relapse, higher risk with pathogenic variants in complement genes

Early reintroduction of eculizumab (within 48 hrs) rapid hematologic remission & creatinine return to baseline

Progress of our patient

Febrile illness in Apr & June 2018

Given Eculizumab infusion early at illness, without progression to hemolysis, no further doses as no hemolysis developed

Further review on overseas experience, decided on future episodic “on-demand” treatment at the early phase of “documented” aHUS recurrence

Regular monitoring of CBP, RFT, LDH, urine haemastix

Thank you