anti-phospholipid syndrome (aps)...renal artery stenosis and hypertension anti-hypertensive agents...
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ANTI-PHOSPHOLIPID SYNDROME (APS)
A focus on renal involvement
Anti-phospholipid syndrome
APS is an autoimmune disease characterized by the
presence of anti-phospholipid antibodies (aPL) and
various clinical manifestation related to arterial or
venous thrombosis
It can be further divided into primary and
secondary APS
Making the diagnosis requires both clinical and
laboratory criteria
Pathogenesis
The antiphospholipid antibodies target β2-glycoprotein I or anticardiolipin detected by ELISA
or antibodies detected by lupus anticoagulant
assay
The risk of a first thrombotic event among
asymptomatic persons who are positive for lupus
anticoagulant, anticardiolipin antibodies, and anti–
β2-glycoprotein I antibodies (triple +ve) is
5.3%/year
Giannakopoulos B, Krilis SA. N Eng J Med. 2013;368:1033-44..
Pathogenesis
“Two-hit” model
Initial first hit disrupts the endothelium
Second hit potentiates thrombus formation
First hit may not be identified
Infection or recent surgery in CAPS
Smoking β2-glycoprotein I
Giannakopoulos B, Krilis SA. N Eng J Med. 2013;368:1033-44.
Giannakopoulos B, Krilis SA. N Eng J Med. 2013;368:1033-44.
Pathogenesis
Recent study revealed that the activation of mTOR
enzymes stimulates intimal hyperplasia leading to
chronic vascular lesion
Merashli M et al_Eur J Clin Invet. 2015;45(6):653-62.
Clinical criteria
Miyakis S et al_J Thromb Haemost. 2006;4:295-306
Laboratory criteria
Miyakis S et al_J Thromb Haemost. 2006;4:295-306
Specific clinical entity
http://slideplayer.com/slide/10696917/
http://www.westernreserveheartcare.com/vp/echo-cardio.htm
Livedo reticularis
aPL-associated cardiac valve disease
aPL-associated thrombocytopenia
Catastrophic APS (CAPS)
Kazzaz NM et al. Curr Opin Rheumatol. 2016;28:218-27
aPL-associated nephropathy
(APS nephropathy)
Epidemiology
Epidemiology
APS
Prevalence: 40-50 cases per 100000 persons
Incidence: 5 new cases per 100000 persons per year
Positive aPL
Prevalence: 1-5% in general population
13% with stroke
11% with myocardial infraction
9.5% with DVT
6% with pregnancy morbidity
Gómez-Puerta JA, Cervera R. Journal of Autoimmunity 2014;48:20-
5.
Epidemiology
Sex distribution
Adult: Female : Male = 4.5: 1 (n=1000)
Children: Female : Male = 1.2: 1 (n=121)
Mean age
Adult: 34 ± 13 years
Children: 10.7 years (Range: 1-17.9 years)
Cervera R et al. Arthritis and Rheumatism. 2002;46(4):1019-27
Acvin T et al. Pediatrics 2008;122:e1100–07
Primary vs Secondary
aPL is associated with various conditions
Gómez-Puerta JA, Cervera R. Journal of Autoimmunity 2014;48:20-
5.
n=1000
European adults
98.5% Caucasian
n=121
US, South American,
European children
Cervera R et al. Arthritis and Rheumatism. 2002;46(4):1019-27
Acvin T et al. Pediatrics 2008;122:e1100–07
Kazzaz NM et al. Curr Opin Rheumatol. 2016;28:218-27
Our patient
Clinical manifestation
Clinical presentation
Variable
Depends on the site of thrombosis
Arterial vs venous
Recurrent fetal loss in women
Thrombocytopenia
Livedo reticularis
Adult cohort
Cervera R et al. Arthritis and Rheumatism. 2002;46(4):1019-27
Paediatric cohort
Acvin T et al. Pediatrics 2008;122:e1100–07
*Evans syndrome: Autoimmune haemolytic anaemia and ITP
Budd-Chiari syndrome (BCS) in APS
Budd-Chiari syndrome (BCS) in APS
Among 43 patients with APS presented with BCS
Female: Male = 2:1
Mean age: 30.8 years
Primary APS: 74%
BCS as first clinical manifestation of APS: 65%
Thrombocytopenia: 53% (?Related to the underlying
portal hypertension)
Espinosa G et al. Medicine (Baltimore). 2001;80(6):345-54.
How about the kidney?
aPL-associated nephropathy
Also called APS nephropathy
Renal involvement in APS
Renal vein thrombosis
Renal artery stenosis and thrombosis
Renal infraction
Systemic hypertension
Thrombotic microangiopathy
Glomerular microthrombosis associated with SLE
It can be the first presentation of APS
Sciascia S et al. Nat. Rev. Nephrol. 2014;10:279-89.
Abeysekera RA et al. Journal of Medical Case Reports. 2015;9:28
Presentation
??CKD / ESRF
Proteinuria Haematuria Loin pain Hypertension
(New or worsened) AKI
Renal vein
thrombosis
Renal artery stenosis
or thrombosis Renal infraction TMA
Investigations:
- Imaging
- Biochemistry
- Histology
- Immunology
Definition
Miyakis S et al_J Thromb Haemost. 2006;4:295-306
George JN, Nester CM. N Eng J Med. 2014;371:654-6.
Systemic lupus
erythematosis
Anti-
phospholipid
syndrome
APS
nephropathy
Thrombotic
microangiopathy
How prevalent?
Acvin T et al. Pediatrics 2008;122:e1100–07
Prevalence of renal
manifestation: 5%
Underestimation due to low
prevalence of renal biopsy
Cervera R et al. Arthritis and Rheumatism. 2002;46(4):1019-27
F:M = 7:1; Mean age = 35±12 years
Renal involvement: 8.7%
Proteinuria 100% (Nephrotic range 35%)
AKI: 15%
CKD / ESRF: 35%
Hypertension: 57%
10/14 subjects had a renal biopsy performed
Membranous GN: 40%
Proliferative GN: 20%
TMA: 20%
Vascular lesion compatible with APS nephropathy: 20%
Sinico RA et al. CJASN. 2010;5:1211-7.
Tektonidou MG et al. Arthritis and Rheumatism. 2004;50(8):2569-79.
151 White SLE patients
aPL +ve (n=81)
APSN
39.5%
No APSN
60.5%
aPL –ve (n=70)
APSN
4.3%
No APSN
95.7%
- More arterial thrombosis, stroke, PE, hypertension, raised Cr and +ve LA
- 66% had acute changes and 87.5% had chronic changes
- Hypertension was more associated with acute APSN and raised Cr was more
associated with chronic APSN. Both were associated with CKD at end of study.
- No associated between WHO class and any APSN (p=0.2)
- No difference in risk of CKD or ESRF between those with / without APSN (mean
duration of FU = 5.3±4.1 years)
In fact…
Conflicting data on whether
aPL is associated with worse renal outcome among SLE patients
Coexisting APS nephropathy and lupus nephritis carries worse prognosis
Still it is advised to distinguish between lupus nephritis (immune-complex disease) alone or with additional APSN (thrombotic disease and vascular lesions)
Additional anticoagulation may be required
Sciascia S et al. Nat. Rev. Nephrol. 2014;10:279-89.
QEH Paediatrics
Anticardiolipin IgG Lupus
anticoagulant Lupus nephritis APSN Thrombosis
F/10 28.2 -ve Class IV ?? No
M/17 <13.3 -ve Class IV No No
F/15 19.3 Detected Class III No No
M/16 36.2 → 21.1 → <13.3 -ve Class IV No No
F/15 N/A N/A Class III + V *+/- No
F/16 <13.3 → <13.3 Detected Class IV *+/- No
*arterial mild fibroelastic intimal hyperplasia
- Inclusion:
- Patients underwent renal biopsy with pathological diagnosis of SLE
- Age: ≤18 years old
- Source: CDARS (using procedure code of renal biopsy)
- Year: 9/2011-8/2016
MANAGEMENT
Management
Primary and Secondary thromboprophylaxis
Control cardiovascular risk factors
Primary: Aspirin, LMWH, Statin, hydroxychloroquine (especially those with SLE)
Secondary: Warfarin (INR 2-3 for venous thrombosis and INR 3-4 for recurrent thrombosis or arterial thrombosis)
Renal artery stenosis and hypertension
Anti-hypertensive agents in addition to anticoagulants
Sciascia S et al. Nat. Rev. Nephrol. 2014;10:279-89.
Merashli M et al. Eur J Clin Inves 2015;45(6):653-62.
Management
Therapeutic options
Steroid
IVIG
Plasmapheresis
Cyclophosphamide
Rituximab
Complement inhibition (Eculizumab)
The role of all these agents in long term outcome of APS is yet to be determined
As APS is a systemic disease, the extent and severity of other organ involvement should also be considered
Steroid
Patients with APS secondary to SLE with lupus nephritis may have been treated with steroid
In CAPS, it is commonly employed with other measures like IVIG / plasmapheresis
Lack of data evaluating its independent effect
In patients with primary APS with APSN, steroid plus azathioprine / cyclophosphamide has been reported. But it is not routinely recommended
?Due to low awareness of APSN in the past
?Low renal biopsy rate in patients with APS
Sciascia S et al. Nat. Rev. Nephrol. 2014;10:279-89.
Kazzaz NM et al. Curr Opin Rheumatol. 2016;28:218-27
IVIG
It has been reported that F(ab’)2 fragment from IVIG
can neutralize the binding of aCL to cardiolipin and inhibit LA activity
IVIG itself carries risk of thrombosis
Most studies were carried out in obstetric APS or CAPS
May have a role in preventing recurrent thrombosis in addition to convention therapy from a recent review
To prevent thrombosis
More days of infusion (Usually 2g/kg over 4-5 days)
Slow infusion using concentration <5%
Tenti S et al_Autoimmunity Reviews. 2016;15:226.
Plasmapheresis
Extended from the known benefit of plasmapheresis for various forms of microangiopathy
CAPS are frequently treated with combination of steroid, plasmapheresis and/or IVIG
Lack of prospective study to evaluate its effectiveness
?Indication, optimal number of sessions and dose
?Usefulness in other clinical entity of APS
Consideration:
Manpower / Availability / Cost
IVIG is better to be given after plasmapheresis
Kazzaz NM et al. Curr Opin Rheumatol. 2016;28:218-27
Rituximab
Anti-CD 20 monoclonal antibody that depletes
CD20+ B-lymphocytes
Mechanism of its action in APS is unclear
Usually used in refractory cases, especially those
with refractory thrombocytopenia and haemolytic
anaemia
Data in APS nephropathy is limited
Katikaneni M et al. The Open Urology and Nephrology Journal. 2015;8(Suppl 1:M6):27-38
Cyclophosphamide
Usually in patients with coexisting SLE who develops
CAPS
In a retrospective review of patients with CAPS,
non-SLE patients who received cyclophosphamide
actually had increased mortality (OR = 9.5,
p=0.005)
Kazzaz NM et al. Curr Opin Rheumatol. 2016;28:218-27
Eculizumab
Recombinant humanized monoclonal antibody binds
to the terminal complement protein C5
Complement contributes to the activation of the
endothelial cells and induces thrombosis
Isolated case reports on its use in CAPS
Some of them were used in patients with renal
transplantation
Lonze BE et al. N Eng J Med. 2010;362(18):1744-5.
Hadaya K et al. American Journal of Transplantation 2011;11(11):2523-7.
Merashli M et al. Eur J Clin Inves 2015;45(6):653-62.
Back to our patient…
Primary APS
Thrombosis
Persistent thrombocytopenia
APS nephropathy with hypertension, proteinuria and
impaired renal function